Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[C@@H:22]([CH2:23][C:24]2([CH2:27][OH:28])[CH2:26][CH2:25]2)[CH2:21][O:20][C:19]1([CH3:30])[CH3:29])=[O:17])([CH3:14])([CH3:13])[CH3:12].S([O-])(O)(=O)=O.[K+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]([O:15][C:16]([N:18]1[C@@H:22]([CH2:23][C:24]2([CH:27]=[O:28])[CH2:26][CH2:25]2)[CH2:21][O:20][C:19]1([CH3:30])[CH3:29])=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(CO)CC2)COC1(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(C=O)CC2)COC1(C)C
Reaction time: 0.17 h

Procedure:
11.1 ml of dimethylsulfoxide in 150 ml of methylene chloride are added dropwise to a solution of 10.1 ml of oxalyl chloride in 130 ml of methylene chloride at -60° C. When the addition has ended, the mixture is subsequently stirred for a further 10 min, a solution of 22.3 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-[(1-hydroxymethylcyclopropyl)methyl]-1,3-oxazolidine in 270 ml of methylene chloride is then added at -60° C. in the course of 20 min and the mixture is stirred for a further 30 min. 43.6 ml of triethylamine are then added at the same temperature and finally, after 30 min, 140 ml of a 20% potassium hydrogen sulfate solution are added to the reaction mixture. Customary working up gives the title compound as a crude product: Rf (A)=0.73.
Reaction SMILES: C([BH3-])#N.[Na+].[Si:5]([O:12][C@H:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:14]=O)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[NH2:22][C@H:23]([CH3:37])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=1.C(OCC)(=O)C>CO.O>[CH3:36][O:35][C:33]([CH2:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][C@H:23]([NH:22][CH2:14][C@H:13]([O:12][Si:5]([C:8]([CH3:9])([CH3:10])[CH3:11])([CH3:6])[CH3:7])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:37])=[CH:27][CH:28]=1)=[O:34]
Reactant: COC(=O)Cc1ccc(OC[C@@H](C)N)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
630 mg of sodium cyanoborohydride were added, whilst ice-cooling, to a solution of 1.01 g of (R)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde (prepared as described in Preparation 25) and 750 mg of methyl 4-(2(R)-amino-1-propoxy)phenylacetate (prepared as described in Preparation 27) in 10 ml of absolute methanol, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was mixed with ethyl acetate and water. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>CO.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: OB(O)c1cccc(F)c1F
Reactant: N#CCc1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CCc1ccccc1-c1cccc(F)c1F

Procedure:
To a suspension of (2-iodo-phenyl)-acetonitrile (Aldrich, 2.4 g, 10 mmol) and 2,3-difluorophenylboronic acid (Aldrich, 2.4 g, 15 mmol) in anhydrous methanol (10 mL) and toluene (20 mL) was added Cs2CO3 (9.8 g, 30 mmol). The mixture was degassed with nitrogen, followed by the addition of tetrakis(triphenylphosphine)palladium (1.2 g, 1 mmol).
Reaction SMILES: [CH2:1]([C:3]1[NH:4]C(O)=[C:6]([F:10])[C:7](=O)[N:8]=1)[CH3:2].O=P(Cl)(Cl)[Cl:14].[CH2:17]([Cl:19])Cl>>[Cl:14][C:7]1[C:6]([F:10])=[C:17]([Cl:19])[N:4]=[C:3]([CH2:1][CH3:2])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc(=O)c(F)c(O)[nH]1
Reactant: ClCCl
Product: CCc1nc(Cl)c(F)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
2-Ethyl-5-fluoro-6-hydroxy-4(1H)-pyrimidinone (20 g, 126.6 mmol) in POCl3 (58 mL, 633 mmol) was heated at 125° C. (oil bath) for 2 h. An additional 68 mL of fresh POCl3 was added to the hot solution. The resulting solution was heated for an additional 2 h until all the starting material was consumed. The excess POCl3 was distilled (62° C.-68° C.) in vacuo to give a light brown residue. After being cooled to room temperature, the residue was diluted with 50 mL of CH2Cl2, then poured into ice water (200 mL). To this mixture was added 200 mL of CH2Cl2 and the subsequent mixture was stirred for 10 min. After separation of the two layers, the aqueous layer was further extracted with 100 mL of CH2Cl2. The combined organic layers were dried over Na2SO4, then filtered through a short silica gel pad, which was then washed with 150 mL of 1% MeOH in CH2Cl2. Evaporation of the solvent provided 4,6-dichloro-2-ethyl-5-fluoropyrimidine (21 g, 85%) as a light yellow liquid. LCMS: (M+H)+: not detected.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1>C(#N)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:3][CH:4]=1
Reactant: c1cn[nH]c1
Reactant: Nc1ccc(Br)cc1
Solvent: CC#N
Product: Nc1ccc(-n2cccn2)cc1

Procedure:
General procedure B (82° C., 42 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 516 mg of 4-bromoaniline (3 mmoles), 136 mg of pyrazole (2 mmoles) and 1.2 ml of acetonitrile.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[N:16]1([CH2:21][C@H:22](O)[CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][N:18]=[CH:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CO.C(Cl)Cl>[N:16]1([CH2:21][C@@H:22]([O:1][C:2]2[C:3]([N+:13]([O-:15])=[O:14])=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O=C1CCCc2c1ccc(O)c2[N+](=O)[O-]
Reactant: CC(C)[C@@H](O)Cn1ccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@@H](Cn1ccnc1)Oc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 6-hydroxy-5-nitro-1-tetralone (0.888 g, 4.29 mmol) in dry THF (10 mL) was added (R)-1-imidazol-1-ylmethyl-2-methyl-propanol (0.737 g, 4.78 mmol) followed by triphenylphospine (1.26 g, 4.78 mmol). After approximately 10 min, diethylazodicarboxylate (0.75 mL, 4.78 mmol) was added slowly. The reaction was allowed to stir at RT for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (SiO2, 20% acetone/CH2Cl2 then 5% MeOH/CH2Cl2) afforded the title compound as a foam (1.02 g, 2.97 mmol, 69%). The structure was confirmed by NMR and mass spectrometry. MS m/z 344 (M++H). 2. 5-Amino-6-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-3,4-dihydro-2H-naphthalen-1-one
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-])=O)[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][C@@H:22]([OH:26])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(C)C.[Pd]>[NH2:27][C:17]1[C:18]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([OH:26])[CH2:21]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCC[C@@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To the reaction mixture from the above step containing (1R,3R)-3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino) cyclohexanol (8.65 mmol) in isopropyl alcohol (30 mL) was added 10% Palladium on activated carbon (718 mg). The reaction mixture was then capped with a 3 way glass valve with a hydrogen gas balloon. The flask was opened to vacuum for two minutes, followed by opening to hydrogen. This purge/flush cycle was repeated 3 times before stirring under a hydrogen atmosphere at room temperature for 2 days. LC/MS showed that the reaction went to completion. The reaction mixture was then filtered through celite 545 and concentrated to give a black foamy solid, which was used as is for the next step. LCMS (Method M, ESI): RT=1.44 min, m+H=386.8.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].S(C1C=CC(C)=CC=1)(OC[CH2:15][Cl:16])(=O)=O.[C:24](=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:16][CH2:15][CH2:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH3:24]
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCl
Yield: 52.2 %

Procedure:
A mixture of 52.88 g (0.426 mole) of guaiacol, 100 g (0.426 mole) of chloroethyl tosylate, 88.3 g (0.639 mole) of powdered potassium carbonate and 600 mL of 2-butanone is stirred mechanically and refluxed for 2 days. The reaction is filtered and the solid is rinsed with 2-butanone. The filtrate is evaporated and the residue taken up in ether and washed with 1N NaOH to remove unreacted guaiacol. The ether layer is dried over sodium sulfate, filtered and evaporated to give an oil which slowly crystallized. The solid is isolated with cold cyclohexane to give 41.47 g (52%) of 1-(2-Chloroethoxy)-2-methoxybenzene as a white solid, m.p. 42-3° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5](/[CH:9]=[C:10](/[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)\[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.C(O)C.C([O-])=O.[NH4+].C(OCC)(=O)C>[Pd].C(O)(=O)C>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)/C(=C\c1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)C(Cc1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Yield: 124 %

Procedure:
A three neck, one liter round bottom flask equipped with condenser, thermometer, nitrogen line and magnetic stirrer was charged with Z-3-(3-trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)-acrylic acid (103, 2.28 g, 6.3 mmol), ethanol (104 mL), palladium black (101.1 mg) and ammonium formate (1.608 g, 25.5 mmol). The reaction mixture was heated to 80° C. for 4 hours. An aliquot was taken and TLC (solvent system was 20% ethyl acetate in hexanes with an acetic acid spike) showed absence of starting material. The solution was cooled to room temperature and vacuum filtered using a glass frit funnel. The solution was concentrated by rotary evaporation and high vaccum, yielding 3-(3-trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)-propionic acid (2.83 g) 105.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C@H:12]([CH3:16])[C:13]([NH2:15])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.CO.ClCCl>C1COCC1>[N:7]1([C@H:12]([CH3:16])[CH2:13][NH2:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C[C@H](C(N)=O)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: C[C@H](CN)N1CCCC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Under a nitrogen atmosphere 31.65 ml 1 M Lithiumaluminiumhydrid solution (THF) are taken and combined with 1 g (7.032 mmol) (R)-2-pyrrolidin-1-yl-propionamide, dissolved in 2 ml THF, at 0° C. The reaction mixture is stirred for 48 h at 50° C. The reaction mixture is combined with 100 ml of methanol and then with the same amount of dichloromethane while cooling with ice. Approx. 25 g silica gel are added to this mixture and the solvent is eliminated in vacuo. This silica gel applied to a suction filter which has previously been charged with approx. 75 g silica gel. The suction filter is washed batchwise with a total of 500 ml of a mixture of dichloromethane, methanol and aqueous conc. ammonia (90:9:1). The majority of the solvent is eliminated at a vacuum of 200 mbar and a sump temperature of approx. 50° C. The product is distilled at 69-71° C. and 10 mbar.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[CH:53]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[CH:53]=2)[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)c1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 66A (0.014 g, 0.046 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate aid 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.018 g, 44% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83(m, 9H), 0.89(m, 9H), 1.62-1.48(m, 2H), 2.31(s, 3H), 2.34-2.24(m, 1H), 2.62-2.53(m, 1H), 2.68-2.65(m, 2H), 2.97-2.73(m, 3H), 3.22-3.12(m, 1H), 3.50(s, 3H), 3.70-3.62(m, 1H), 3.87-3.83(d, J=9.93 Hz, 1H), 4.08(s, 1H), 4.33-4.11(m, 4H), 4.56-4.53(d, J=7.72 Hz, 1H), 6.65-6.62(d, J=9.56 Hz, 1H), 7.04-7.02(m, 3H), 7.11-7.07(m, 4H), 7.25-7.21(m, 4H), 7.33-7.28(m, 1H), 7.49-7.46(d, J=9.56 Hz, 1H), 7.91-7.82(m, 4H), 8.64-8.63(d, J=4.04 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][N:33]1[CH2:38][CH2:37][O:36][C:35]2[CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=[CH:42][C:34]1=2>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:40]2[CH:41]=[CH:42][C:34]3[N:33]([CH3:32])[CH2:38][CH2:37][O:36][C:35]=3[CH:39]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CN1CCOc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)OCCN2C
Yield: 69.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.138 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.075 g (68%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[Li]CCCC.B.Cl[C:14]1[C:15]2[N:23]=[N:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:32][CH3:33])[N:26]=3)[C:16]=2[N:17]=[C:18]([NH2:20])[N:19]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][O:32][CH2:31][C:27]1[N:26]=[C:25]([CH2:24][N:21]2[C:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:14]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[N:3]=4)[C:15]=3[N:23]=[N:22]2)[CH:30]=[CH:29][CH:28]=1
Reactant: COCc1cccc(Cn2nnc3c(Cl)nc(N)nc32)n1
Reactant: Cc1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCc1cccc(Cn2nnc3c(-c4nc(C)cs4)nc(N)nc32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
A solution of 4-methylthiazole (0.15 mL, 1.65 mmol) in dry THF (7.5 mL) was cooled to −78° C. under nitrogen, treated with n-BuLi (1.0 mL, 1.65 mmol) and stirred for 30 minutes, then ZnCl (1-M, 1.65 mL, 1.65 mmol) was added, and the reaction mixture was warmed to room temperature. 7-Chloro-3-(6-methoxymethylpyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine (250 mg, 0.825 mmol) was then added followed by Pd(PPh3)4 (48 mg, 0.04 mmol) and the reaction mixture heated to reflux for 1 h. The reaction mixture was cooled to room temperature, quenched with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated in vacuo. The crude product was purified by chromatography (eluant:EtOAc-heptane 1:1 to 2:1) to give the title compound (38 mg, 13%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:12][CH:13]([CH2:18][C:19]([O:21]C)=[O:20])[C:14]([O:16]C)=[O:15].CO>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:18](\[CH:13]([CH3:12])[C:14]([OH:16])=[O:15])/[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CC(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C(=O)O)/C(=C\c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% in paraffin oil, 31 g, 775 mmol) in toluene (150 mL) was added a solution of 4-fluorobenzaldehyde (30 g, 242 mmol) and dimethyl methylsuccinate (58 g, 362 mmol) in toluene (150 mL) over 1 hour at 0° C. under nitrogen. The reaction was initiated by addition of a drop of methanol at room temperature and was stirred at room temperature for 2 hours. The reaction was quenched by slow addition of 2.0 N aqueous NaOH (300 mL) at 0° C. The resulting mixture was stirred at 110° C. for 4 hours. The mixture was then cooled to room temperature and the aqueous layer was diluted with water (300 mL) and washed with Et2O (2×300 mL). The aqueous phase was cooled in an ice-water bath. Addition of concentrated HCl was followed by extraction with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (50 mL) followed by brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-hexanes to give 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid. The procedure above was repeated using a separate amount of 4-fluorobenzaldehyde (30 g, 242 mmol). The products of the two reactions were combined to provide 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid as a pale yellow solid (28 g, 24% overall). MS cald. for C12H12FO4 [(M+H)+] 239, obsd. 239.2.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([NH:8][C@H:9]([B:14]2[O:18][C@@H:17]3[CH2:19][C@@H:20]4[CH2:23][C@H:22]([C@:16]3([CH3:26])[O:15]2)[C:21]4([CH3:25])[CH3:24])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:5][CH2:4]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:27]([NH:2][C:3]1([C:6]([NH:8][C@H:9]([B:14]2[O:18][C@@H:17]3[CH2:19][C@@H:20]4[CH2:23][C@H:22]([C@:16]3([CH3:26])[O:15]2)[C:21]4([CH3:24])[CH3:25])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:5][CH2:4]1)(=[O:29])[CH3:28]
Reactant: CC(C)C[C@H](NC(=O)C1(N)CC1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC1(C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of 1-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}cyclopropane-carboxamide hydrochloride (0.50 g, 1.30 mmol) in DMF (5.0 mL) was added acetic anhydride (0.15 g, 1.43 mmol). The reaction mixture was cooled to 0° C., and DIEA (0.34 g, 2.6 mmol) was added slowly over 1 h. The reaction was allowed to stir at 0° C. After 1.5 h, the reaction mixture was diluted with H2O (20 mL) and washed with EtOAc (2×30 mL). The organic layers were combined and washed with H2O (2×20 mL), dried over MgSO4, filtered, and concentrated to give the title compound (0.473 g, 93%). LC/MS: Rt=1.78 min, ES+391 (Formic Acid method).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][C:7]1[C:11]2[C:12](=[O:26])[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[NH:9][N:8]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][C:7]1[C:11]2[C:12](=[O:26])[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[NH:9][N:8]=1
Reactant: COc1cccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2c(Cc3cccc(O)c3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 75.6 %

Procedure:
To a solution of 3-(3-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (53 mg, 0.14 mmol, prepared in Example 20) in acetic acid (2 ml) was added 47% hydrogen bromide (1.5 ml), and the mixture was heated under reflux overnight. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-(3-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (39 mg, 76%).