Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11]CC3C=CC=CC=3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:19](=[O:21])[NH2:20]>CO.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:19](=[O:21])[NH2:20]
Reactant: Cn1c(C(N)=O)cc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(C(N)=O)cc2cc(O)ccc21
Reaction time: 2 h
Yield: 95 %

Procedure:
A suspension of 1-methyl-2-carbamoyl-5-benzyloxy-1H-indole (1.94 g; 6.96 mmol) and 10% Pd/C (0.5 g) in methanol (100 ml) was hydrogenated for 2 hours. After filtration of the catalyst on celite, the filtrate was evaporated to give 1-methyl-2-carbamoyl-5-hydroxy-1H-indole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:20][C:21](=[O:31])[CH2:22]P(=O)(OCC)OCC)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:32][C:33]([N:35]([CH3:37])[CH3:36])=O.[Li+].[Cl-].[OH-].[K+]>O.C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[NH:9][C:10]1[C:11]2[CH:19]=[C:18]([NH:20][C:21](=[O:31])/[CH:22]=[CH:32]/[CH2:33][N:35]([CH3:37])[CH3:36])[N:17]=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Br)c3)ncnc2cn1)OCC
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc(F)c(Br)c3)ncnc2cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (15.7 g, 97.5 mmol) and water (16.4 mL) at room temperature under a nitrogen atmosphere was added aq. 37% HCl (16.4 mL, 195 mmol). After addition the mixture was stirred at 40° C. (bath) for 25 hours. It was then cooled to 0° C. (bath) to give Solution A. KOH (14.0 g, 250 mmol) was dissolved in water (75 mL) at room temperature under a nitrogen atmosphere. It was then cooled to 0° C. (bath) to give Solution B. To a stirred heterogeneous mixture of compound 160 (19.97 g, 39.0 mmol) at room temperature under a nitrogen atmosphere was added a minimum amount of DMA (60 mL) to give a homogeneous solution. LiCl (1.65 g, 39.0 mmol) was then added and the resulting mixture was stirred at 0° C. (bath) for 15 min. The cold Solution B was then added and the reaction was stirred at 0° C. for 2 min. Cold Solution A was then added and the final reaction mixture was stirred further at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC (DCM/MeOH=10:1). After 30 min more KOH (s) (5.0 g, 89 mmol) was added and the reaction was stirred further at 0° C. for 1.5 hours. It was then poured into water (1,000 mL). Petroleum ether (1,000 mL) was added and the mixture was stirred at room temperature for 20 min. The petroleum ether layer was decanted before more petroleum ether (600 mL) was added and the mixture was again stirred for 15 min. The solid was collected by filtration, washed with water (5×200 mL) and dried under reduced pressure over silica gel/KOH to give (2E)-N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)-2-butenamide (161) (16.9 g, 97%).
Reaction SMILES: BrCC.[Mg].Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21].[CH3:22][C:23]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[O:25][N:24]=1.[Cl-].[NH4+]>C1COCC1>[CH3:22][C:23]1[CH:27]=[C:26]([C:28]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:29])[O:25][N:24]=1
Reactant: Cc1cc(C(=O)Cl)on1
Reactant: Cc1ccc(C)c(OCc2ccccc2Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)c2cc(C)no2)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 17.4 %

Procedure:
THF (2 ml) and bromoethane (0.1 ml) were added to magnesium (0.49 g, 0.02 mol) in a stream of nitrogen, and the mixture was stirred at 50° C. for 10 minutes. Then, a mixture of 1-bromo-2-(2,5-dimethylphenoxymethyl)benzene (2.91 g, 0.01 mol) and THF (8 ml) was added at 50 to 60° C. over 30 minutes, and the mixture was stirred at 50 to 60° C. for 1 hour. After completion of the reaction, the reaction mixture was added to a mixture of 3-methylisoxazol-5-carbonyl chloride (1.45 g, 0.01 mol) and THF (15 ml) at −70 to −60° C. over 15 minutes, and then the mixture was stirred at −70 to −60° C. for 0.5 hours. After completion of the reaction, saturated aqueous ammonium chloride solution (150 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone (0.56 g, 17.4%) as colorless crystals. mp. 106-108° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[N:10][C:9]=1[NH:20][NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OCC)(=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([C:8]1[C:9]2[N:10]([C:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:21][N:20]=2)[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1nnc(-c2ccccc2)cc1Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)Cc1nnc2c(Cc3ccccc3)cc(-c3ccccc3)nn12

Procedure:
In a manner analogous to that described in Example 1, by the ring condensation of 4-benzyl-3-hydrazino-6-phenyl-pyridazine [Indian J. Chem., 15B, 352 (1977)] with diethyl malonate there is obtained ethyl 8-benzyl-6-phenyl-s-triazolo[4,3-b]pyridazine-3-acetate, MS: 372 (M)+, which is saponified with a base to the above acid, MS: 316 (M-CO)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[C:6](Br)[CH:5]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>[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.O>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([Cl:15])[CH:17]=2)[C:7]([O:11][CH3:12])=[C:8]([F:10])[CH:9]=1)=[O:14]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: COC(=O)c1cc(F)c(OC)c(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(F)c(OC)c(-c2ccc(OC)c(Cl)c2)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
500 mg of 3-Bromo-5-fluoro-4-methoxy-benzoic acid methyl ester, 532 mg of 3-chloro-4-methoxyphenylboronic acid, 110 mg of tetrakis(triphenylphosphine) palladium(0), and 2.5 g Cs2CO3 were dissolved using 16.5 ml of DMF and 3.5 ml of water. The reaction mixture was stirred at 45° C. for 2 h and then poured into 75 ml of water. The reaction mixture was then extracted three times using 50 ml of EA each. The organic layer was washed twice using 25 ml of a half-saturated aqueous NaCl-solution, dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:3 yielded 500 mg of the title compound, viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9](I)([F:11])[F:10].OO>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].CS(C)=O>[OH:1][C:2]1[C:7]([C:9]([F:11])([F:10])[F:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccccn1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: OO
Agent: c1cc[cH-]c1
Solvent: CS(C)=O
Product: Oc1ncccc1C(F)(F)F
Temperature: 25 °C
Yield: 64 %

Procedure:
0.19 g (2.0 mmol) of 2-hydroxypyridine and 0.11 g (0.6 mmol) of ferrocene were weighed and placed in a two-neck flask and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 8.0 ml of dimethyl sulfoxide, 2.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.4 ml of a 30% hydrogen peroxide aqueous solution, and the mixture was stirred for 20 minutes. During the stirring, the temperature of the reaction system rose up in the range of from 40° C. to 50° C. Thereafter, the resulting solution was cooled to room temperature. Formation of 2-hydroxy-3-trifluoromethylpyridine (19F-NMR yield: 64%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. The subsequent procedure was conducted in the same manner as in Example 1 and 2-hydroxy-3-trifluoromethylpyridine was obtained as a white solid (0.081 g, yield: 50%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:25](=[CH:26][CH:27]=1)[O:24][C:13]1([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)[CH2:12][C:11]2=[O:28].Cl>O.O1CCOCC1>[C:20]([O:19][C:17]([N:15]1[CH2:14][C:13]2([CH2:12][C:11](=[O:28])[C:10]3[C:25](=[CH:26][CH:27]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:29])=[O:4])[CH:9]=3)[O:24]2)[CH2:16]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
1 M NaOH (1.60 ml) was added to a solution of (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (Intermediate 4, Step B, 450 mg, 1.20 mmol) in water (11 ml) and dioxane (22 ml). The mixture was stirred at RT for 5 h. Aqueous HCl 10% was added until reaching pH 7, dioxane was removed under vacuum and the residue was diluted with water. The aqueous layer was acidified to pH 5 with 10% aqueous HCl and the product was extracted with DCM (3×30 ml). The collected organic phases were dried over Na2SO4 and concentrated to give (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (430 mg) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:14])[N:12]=2)=[C:4]([NH:21][CH:22]([CH3:24])[CH3:23])[CH:3]=1.[N:25]1[S:26][N:27]=[C:28]2[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:29]=12.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:25]1[S:26][N:27]=[C:28]2[CH:33]=[C:32]([NH:34][C:2]3[N:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([CH3:20])=[C:11]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:14])[N:12]=4)=[C:4]([NH:21][CH:22]([CH3:24])[CH3:23])[CH:3]=3)[CH:31]=[CH:30][C:29]=12
Reactant: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)NCCCO
Reactant: Nc1ccc2nsnc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1oc(-c2cnc(Nc3ccc4nsnc4c3)cc2NC(C)C)nc1C(=O)NCCCO
Temperature: 115 °C

Procedure:
To a stirred solution of (2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide (31) (100 mg, 0.283 mmol) in 1,4-Dioxane (10 mL), benzo[c][1,2,5]thiadiazol-5-amine (0.283 mmol, 1 equiv.), Na2CO3 (1.134 mmol, 4 equiv.) and Xanthphos (0.113 mmol, 0.4 equiv.) were added and degassed for 10 min. Pd2(dba)3 (0.113 mmol, 0.4 equiv.) was added and degassed once again for 10 min. Heated the reaction mixture at 115° C. for overnight. The reaction was cooled and filtered through small pad of celite. The filtrate obtained was concentrated to provide crude material. The crude material was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent to afford 2-(6-(benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide [Example 90]. 1H NMR: 400 MHz, CD3OD: δ 1.42 (d, J=6.40 Hz, 6H), 1.83-1.84 (m, 2H), 2.71 (s, 3H), 3.51 (t, J=1.20 Hz, 2H), 3.72 (t, J=7.20 Hz, 2H), 3.81-3.83 (m, 1H), 6.28 (s, 1H), 7.67 (dd, J=2.00, 9.40 Hz, 1H), 7.89 (dd, J=9.60, 9.20 Hz, 1H), 8.47 (s, 1H), 8.64 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 1.896 min; LCMS (ES-API), m/z 466.0 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.335 min; Purity: 98.7%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:9](=[O:14])[NH:10][CH:11]=[CH:12][CH:13]=1.ClC(Cl)(Cl)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O>ClCCl>[CH3:7][C:8]1[C:9](=[O:14])[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: Cc1ccc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Product: Cc1cccn(CC(F)(F)F)c1=O
Reaction time: 2 h
Yield: 55.9 %

Procedure:
Cesium carbonate (11.4 g, 34.9 mmol) was added to a solution of 3-methylpyridin-2(1H)-one (3.81 g, 34.9 mmol) and 2,2,2-trifluoroethyl trichloromethanesulfonate (9.81 g, 34.9 mmol) in dichloromethane (80 mL). After 2 h, water was added. The mixture was extracted with ether (3×), and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane 25%→methanol/dichloromethane) gave the title compound (3.73 g). MS192.3 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][C:10]3[C:15]4[C:20]([NH:21][C:9]=3[C:8]=2[CH:26]=1)=[CH:19][CH:18]=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=4)[CH:2]=[CH2:3].[OH2:27]>CN(C=O)C.Cl[Pd]Cl>[O:27]=[C:2]([CH3:3])[CH2:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][C:10]3[C:15]4[C:20]([NH:21][C:9]=3[C:8]=2[CH:26]=1)=[CH:19][CH:18]=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=4
Reactant: C=CCc1ccc2c(c1)-c1[nH]c3ccc(C(F)(F)F)cc3c1CC(=O)N2
Reactant: O
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc2c(c1)-c1[nH]c3ccc(C(F)(F)F)cc3c1CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 2-(2-propenyl)-9-trifluoromethyl-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one (108 mg, 0.3 mmol) in DMF (6 ml) and H20 (1 ml) was added PdCl2 (6 mg, 0.03 mmol) and CuC12 (48 mg, 0.36 mmol). After stirring the mixture overnight at room temperature it was poured into 30 ml of water and extracted with ethyl acetate (50 ml X 3). The organic layers were combined, washed with water (10 ml×3) and dried over NaSO4. Evaporation of the solution yielded a residue, which was purified by flash chromatography (ethyl acetate: petrol ether=70:30) to yield 78 mg of 2-(2-oxopropyl)-9-trifluoromethyl-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one (69%), mp295-297° C. (ethanol); IR 3310, 1710, 1650, 1310, 800 cm−1; 1H NMR (400 MHz) 2.20 (s 3 H), 3.58 (s, 2 H), 3.78 (s, 2 H), 7.18-7.30 (m, 2 H), 7.46 (d, J=8.6 Hz, 1 H), 7.57 (s, 1 H), 7.61 (d, J=8.1 Hz, 1 H), 8.13 (s, 1 H), 10.14 (s, 1 H), 12.07 (s, 1 H); 13C NMR (100 MHz) 29.5, 31.2, 49.9, 108.4, 112.1, 115.8, (q, J. 3 Hz), 118.3 (q 3 Hz), 120.0 (q, J=37 Hz), 122.0, 122.3, 125.5 (q, J=270 Hz), 125.8, 127.8, 130.0, 130.3, 134.3, 134.5, 138.7, 171.3, 205.9; Anal. (C2OH15N2O2F3, 372.346): calcd. C, 64.51; H 4.06; N, 7.52; found C 64.30; H, 4.23; N, 7.50
Reaction SMILES: C([O:5][CH2:6][C:7]1[N:11]=[C:10]([NH2:12])[NH:9][N:8]=1)(=O)CO.[CH3:13][C:14]([CH2:16][C:17]([CH3:19])=O)=O>CCO.CC(O)=O>[CH3:13][C:14]1[CH:16]=[C:17]([CH3:19])[N:9]2[N:8]=[C:7]([CH2:6][OH:5])[N:11]=[C:10]2[N:12]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1nc(COC(=O)CO)n[nH]1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared by a slight modification of a reported procedure (Lippman, E.; Becker, V., Z. Chem., 1974, 14, 405): A solution of (5-amino-1H-1,2,4-triazol-3-yl)methanol glycolate (30.7 g, 0.161 mol, from Step 1, above) and 2,4-pentadione (32.3 g, 0.323 mol, 2 equiv) in a mixture of EtOH (750 mL) and AcOH (250 mL) was refluxed 20 h. At the beginning the reaction mixture was clear solution, then gradually turned yellow towards the end of the heating period. The solvent was removed under reduced pressure, and the resulting yellow paste triturated with EtOH (100 mL) and stirred for 15 min. The slurry was chilled to 5° C. (ice bath) with stirring for 30 min, filtered, and washed with cold (0–5° C.) EtOH. The product was dried in vacuo at 25–30° C. to give 24 g (83.7%).
Reaction SMILES: C(N[C@H]([C@H]1OC(=O)CC1)CC1C=CC(OC)=CC=1)(OC(C)(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:35]([NH:42][C@H:43]([C@H:59]1[O:63][C:62](=[O:64])[C@H:61]([CH2:65][C:66]2[CH:71]=[CH:70][C:69](OCC3C=CC=CC=3)=[CH:68][CH:67]=2)[CH2:60]1)[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52]C2C=CC=CC=2)=[CH:47][CH:46]=1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(Br)C1C=CC=CC=1>C1COCC1.CN1C(=O)N(C)CCC1>[C:35]([NH:42][C@H:43]([C@H:59]1[O:63][C:62](=[O:64])[C@H:61]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH2:60]1)[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1
Agent: BrCc1ccccc1
Agent: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](Cc3ccccc3)C(=O)O2)cc1

Procedure:
In analogy with Example 5d), 4.17 g (12.44 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl]dihydrofuran-2-(3H)-one, dissolved in 22.4 ml of THF and 2.5 ml of DMPU, are deprotonated, at -70° C., with 24 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated -75° C., 1h) with 1.5 ml (12.44 mmol) of benzyl bromide. Protonation, at -75° C., with 4.6 ml of propionic acid and 4.6 ml of water, extraction and column chromatography (SiO2, methylene chloride/ether 25:1) yields the title compound: TLC Rf (C)=0.74; tRet (II)=16.6 min; FAB-MS (M+H)+ =426.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:24])[N:7]2[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOCC.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.[Pd]>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:24])[N:7]2[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23]
Reactant: COC(=O)c1cc(Br)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccccc2Cl)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2c1

Procedure:
Methyl 5-bromo-1-(2,6-dichlorophenyl)-2-oxo-1,2-dihydroquinoline-7-carboxylate (80 mg), 2-chlorophenylboronic acid (58 mg), palladium tetrakis(triphenylphosphine) (22 mg) and 1M aqueous sodium carbonate (450 μL) were mixed in ethylene glycol dimethyl ether (2 mL), degassed with argon and then heated to reflux for 90 min. The cooled reaction mixture was diluted with ether, filtered through celite and concentrated. The residue was purified by silica gel chromatography eluting with 70% hexane:30% ethyl acetate to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.82 (d, J=1.4 Hz, 1H); 7.65-7.39 (m, 8H); 7.23 (s, 1H); 6.82 (d, J=9.9 Hz, 1H), 3.90 (s, 3H). Mass spectrum: m/z 458 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[CH2:27]([Mg]Cl)[CH:28]=[CH2:29]>C(OCC)C>[CH2:29]([CH:6]1[N:7]2[CH2:20][CH2:19][C:18]3[C:13]([C:8]2=[CH:9][C:10]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:24][CH3:25])[C:5]1=2)=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=3)[CH:28]=[CH2:27]
Reactant: C=CC[Mg]Cl
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Agent: [Cl-]
Solvent: CCOCC
Product: C=CCC1c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of berberine hydrochloride (500 mg, 1.3 mmol) in anhydrous diethyl ether (50 mL) at 0° C. was added allylmagnesium chloride solution (1.7 M in tetrahydrofuran, 8 mL, 13 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8-allyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (250 mg, 49%). LC/MS m/e calcd for C23H23NO4 (M+H)+: 378.44, observed: 378.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=6.32 Hz, 2 H) 2.66-2.75 (m, 1 H) 2.79-2.87 (m, 1 H) 3.26-3.32 (m, 1 H) 3.35-3.44 (m, 1 H) 3.78 (d, J=6.32 Hz, 6 H) 4.78-4.85 (m, 2 H) 4.86 (s, 1 H) 5.68-5.80 (m, 1 H) 5.87 (s, 1 H) 6.00 (d, J=3.54 Hz, 2 H) 6.68 (d, J=8.34 Hz, 1 H) 6.77 (s, 1 H) 6.84 (d, J=8.59 Hz, 1 H) 7.23 (s, 1 H).
Reaction SMILES: [Si](OC[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.C([Mg]Cl)C1C=CC=CC=1.[CH2:27]([O:29]CC)C.[Cl-].[NH4+]>O1CCCC1.O>[C:13]1([CH2:14][CH2:27][OH:29])[CH:12]=[CH:11][CH:10]=[CH:17][CH:16]=1
Reactant: CCOCC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C=O)cc1
Agent: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccccc1
Temperature: -40 °C

Procedure:
4-(t-Butyldimethylsilyloxymethyl)benzaldehyde (Synthesis (1995), 12, 1529-33) (6.65 gm, 26 mmol) was dissolved in dry tetrahydrofuran (50 mL) and the solution cooled to −40° C. Benzyl magnesium chloride in diethyl ether (1 M, 35 mL, 35 mmol) was added slowly. The reaction was allowed to warm to 0° C. over three hours. The reaction was then quenched by the addition of ammonium chloride (2.3 gm, 43 mmol) in water (60 mL). The product was extracted into diethyl ether, washed with NaHCO3 solution, dried (over Na2SO4), and filtered. The solution was evaporated to give 1-[4-t-butyldimethylsilyloxymethyl)-phenyl]-2-phenylethanol as an oil which was used as is. 1H-NMR (500 MHz, CDCl3): δ 7.19-7.34 (9H, m), 4.90 (1H, dd, J=4.9, 8.3 Hz), 4.75 (2H, s), 2.98-3.07 (2H, dt), 0.95 (6H, s), 0.11 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18](OC)=[O:19])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CCOC(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[N:5]=[C:4]([CH:18]=[O:19])[N:3]=1
Reactant: COC(=O)c1nc(C)cc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C=O)n1
Temperature: -75 °C
Reaction time: 1.75 h

Procedure:
To a solution of methyl 4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2-carboxylate (which may be prepared by the method described in Description 29) (6.1 g, 20.59 mmol) in dry THF (120 mL) cooled to −75° C. was added diisobutylaluminium hydride (1M in toluene) (41.18 mL, 41.18 mmol) drop-wise over 10 minutes. The solution was stirred at the same temperature for 1.75 h then EtOH (0.96 ml) was added. After 1 minute the reaction mixture was poured into saturated Rochelle salt solution, (250 ml) and water (250 ml). EtOAc (250 ml) was added and the mixture stirred vigorously for 0.5 h then filtered under suction through celite. The filtrate was transferred to a separating funnel and the layers separated. The aqueous fraction was further extracted with EtOAc (200 ml) and the combined organic extracts were dried (MgSO4) and evaporated to a pale yellow, sticky solid. This was stirred with iso-hexane (30 ml) for 5 minutes then sonicated for 5 minutes. It was filtered, washed with iso-hexane (10 ml) and dried at RT under vacuum for 2 hours to give 4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2-carbaldehyde (D30) (4.66 g);