Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Br:12]Br>N1C=CC=CC=1.[Cl-].[Na+].O>[Br:12][C:9]1[C:8]([OH:11])=[CH:7][CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:10]=1
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(O)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(O)c(Br)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-(1,1-dimethylethyl)-3-pyridinol, (3.8 g) in pyridine (150 ml) was added bromine (1.29 ml), diluted in pyridine, dropwise at 20 C. The reaction mixture was allowed to stir at 25-30 C. for 1 h. The reaction had gone to completion by tlc. It was poured into brine and extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated under reduced pressure. The crude material was subjected to flash chromatography using a 0-5% gradient of ethyl acetate in hexane to give the title compound, 2.9 g
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]=2)=[CH:5][N:4]=1)#[CH:2].I[C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([CH3:32])([OH:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[F:9][C:8]1[C:3]([C:1]#[C:2][C:18]2[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][C:28]([CH3:32])([OH:31])[CH2:29][CH2:30]3)=[CH:20][CH:19]=2)=[N:4][CH:5]=[C:6]([C:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]=2)[CH:7]=1
Reactant: C#Cc1ncc(C2=CCC(C)CC2)cc1F
Reactant: CC1(O)CCN(CCOc2ccc(I)cc2)CC1
Product: CC1CC=C(c2cnc(C#Cc3ccc(OCCN4CCC(C)(O)CC4)cc3)c(F)c2)CC1

Procedure:
The product was prepared analogously to Example 48.1c from 130 mg (0.60 mmol) of 2-ethynyl-3-fluoro-5-(4-methylcyclohex-1-enyl)pyridine and 217 mg (0.60 mmol) of 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidin-4-ol (IP 15) (24 at RT, triethylamine as base). Yield: 15 mg (6% of theoretical); C28H33FN2O2 (M=448.572); calc.: molpeak (M+H)+:449; found: molpeak (M+H)+:449; HPLC-MS: 5.08 minutes (method H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].C[O-].[Na+].[Na].[CH:15](Br)([CH3:17])[CH3:16]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:15]([CH3:17])[CH3:16])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: CC(C)Br
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(C)Oc1ccccc1C(C)C

Procedure:
A solution of 2-isopropylphenol (75 g, 0.54 mol) in 60 ml methanol was added, under nitrogen, to a solution of sodium methoxide, prepared by reacting 13.1 g (0.57 mol) sodium with 150 ml dry methanol. To this stirred solution was added isopropyl bromide (82.2 g, 0.66 mol) dropwise over several hours, after which the reaction mixture was heated at reflux overnight. The cooled mixture was filtered to remove solids and methanol was removed on a rotary evaporator. The residue, containing both liquid and solid, was treated with about equal volumes of diethyl ether and water, with the aqueous phase then separated and discarded. The ether phase was washed with Claisen solution, water being added to facilitate separation of phases, and the organic phase retained. The combined aqueous phases was extracted with ether, the extract being added to the prior retained organic phase, and the combined material was dried over anhydrous magnesium sulfate. Ether was removed by evaporation and the residue was distilled to afford isopropyl (2-isopropylphenyl) ether.
Reaction SMILES: Cl.[C:2]([OH:10])(=[O:9])[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19].Cl>O.ClCCl>[CH2:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][C:3]([C:2]([OH:10])=[O:9])=[CH:4][CH2:5]1)=[O:19])[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)C1=CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)N1CC=C(C(=O)O)CC1
Reaction time: 5 h
Yield: 102.4 %

Procedure:
1,2,5,6-Tetrahydroisonicotinic acid hydrochloride (150 g, 0.92 mol) is added to an aqueous solution of sodium carbonate (194 g, 1.83 mol) in water (920 ml), and thereto is added dropwise 2-propenyl chloroformate (116 g, 0.96 mol) under ice-cooling over a period of one hour. After the addition, the mixture is further stirred under icecooling for five hours. Separately, conc. hydrochloric acid (191 g) and dichloromethane (1000 ml) are cooled, and thereto is added dropwise the above reaction mixture in portions. The mixture is separated, and the aqueous layer is extracted twice with dichloromethane. The organic layers are combined, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent to give 1-(2-propenyloxycarbonyl)-1,2,5,6-tetrahydro-isonicotinic acid (198.9 g, quant.) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1.C1COCC1>[C:17]([O:1][C:2]1[CH:11]=[C:10]([O:12][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCc1cc(=O)oc2cc(OC(=O)C(C)(C)C)cc(OC(=O)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 177.9 %

Procedure:
To a solution of 5,7-dihydroxy-4-propylcoumarin (2) (1.10 g, 5 mmol) in pyridine (12 mL) and THF (6 mL) was added pivaloyl chloride (0.673 mL, 5.5 mmol) and the reaction mixture was allowed to stir at room temperature for 24 h. TLC revealed formation of a new less polar spot and unreacted starting material. In an effort to drive the reaction to completion, pivaloyl chloride (0.50 mL) was added and the reaction continued to stir at room temperature for another 72 h. The pyridinium hydrochloride was removed by filtration and washed a few times with ethyl acetate. The organic solutions were combined and washed, successively, with 1 M HCl (2×25 mL), water (25 mL), aqueous saturated sodium bicarbonate (25 mL). After being dried over sodium sulfate and concentrated under vacuum, the crude product was purified by silica gel chromatography (2:1 hexane/ethyl acetate) to obtain 8b as a white solid (1.90 g, 98% yield). mp 110-112° C.; Rf=0.49 (4:1 hexane/ethyl acetate); 1H-NMR (CDCl3),: 1.03 (3H, t, J=7.8 Hz), 1.36 (9H, s), 1.41 (9H, s), 1.69 (2H, sextet, J=7.4 Hz), 2.81 (2H, t, J=7.8 Hz), 6.22 (1H, s), 6.60 (1H, d, J=2.4 Hz), 7.03 (1H, d, J=2.1 Hz); 13C-NMR (CDCl3): 13.5, 20.7, 26.4, 26.8, 26.9, 36.4, 39.2, 39.4, 108.6, 111.5, 113.4, 114.2, 149.4, 152.7, 154.9, 155.4, 159.9, 177.1; IR (film): 3090, 2971, 2941, 2876, 1757, 1615, 1481, 1422, 1273 cm−1; MS m/e 389 (M+1); Anal. Calcd. for C22H28O6: C, 68.02; H, 7.26. Found: C, 67.77; H, 7.18.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Br[C:19]([CH2:21][CH3:22])=[CH2:20].O>CC(=O)CC>[F:7][C:8]([F:16])([F:17])[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:20][CH:19]=[CH:21][CH3:22]
Reactant: C=C(Br)CC
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC=CCOc1cccc(C(F)(F)F)c1

Procedure:
18 g of potassium carbonate were added to 15 ml of 3-trifluoromethylphenol and 25 ml of 2-butanone with stirring and then 15.1 ml of 2-bromobutene in 70 ml of 2-butanone were added. The mixture was refluxed for 90 minutes, then stirred for 72 hours at ambient temperature. 300 ml of water were then added, followed by extraction with methylene chloride. The extracts were dried and concentrated to dryness to obtain 21.73 g of the expected product.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH3:23])=[O:21])=[CH:14]2>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH3:23])=[O:21])=[CH:14]2
Reactant: ClCc1ccccn1
Reactant: COC(=O)c1cc2cc(O)ccc2[nH]1
Agent: Cl
Product: COC(=O)c1cc2cc(OCc3ccccn3)ccc2[nH]1
Yield: 18.1 %

Procedure:
2-Chloromethylpyridine hydrochloride (515 mg) and methyl 5-hydroxy-1H-indole-2-carboxylate (600 mg) were processed in the same manner as in Production Example 1-1 to obtain the entitled compound (160 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[C:14](Cl)([CH3:17])([CH3:16])[CH3:15]>O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.10 g (22.6 mmol) of aluminum chloride are added all at once to a mixture of 63.5 g (339 mmol) of p-bromoanisole and 31.4 g (330 mmol) of tert.butyl chloride. The mixture is stirred at ambient temperature until the evolution of gas ceases (about 15 minutes). The mixture is then heated at 80° C. for 15 minutes and poured into ice. 300 ml of water are added and the mixture is extracted with ether.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][C:28]1[C:29]([C:40]2[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=2)=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[C:35]([CH:38]=O)[CH:34]=[CH:33]2>>[F:26][C:2]([F:1])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:38]([C:35]3[CH:34]=[CH:33][C:32]4[C:37](=[C:28]([CH3:27])[C:29]([C:40]5[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=5)=[CH:30][CH:31]=4)[N:36]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: Cc1c(-c2cnn(C)c2)ccc2ccc(C=O)nc12
Product: Cc1c(-c2cnn(C)c2)ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B, Step F, using tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate and 8-methyl-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbaldehyde. LCMS APCI (+) m/z 507 (M+H).
Reaction SMILES: B.O1CCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:20][N:19]([CH2:21][CH2:22][CH3:23])[C:18](=O)[CH2:17][O:16]2)[CH:12]=[CH:13][CH:14]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]2[O:16][CH2:17][CH2:18][N:19]([CH2:21][CH2:22][CH3:23])[CH2:20]2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCCN1CC(c2cccc(OC)c2)OCC1=O
Agent: B
Solvent: C1CCOC1
Product: CCCN1CCOC(c2cccc(OC)c2)C1
Yield: 83.3 %

Procedure:
Borane-tetrahydrofuran complex (1M in THF) (200 ml, 0.19 mol) was added dropwise to the morpholin-3-one from example 5 (15.8 g, 0.06 mol) in dry THF (100 ml) under an atmosphere of nitrogen, over 30 minutes. The reaction mixture was brought to reflux for 3 hours then cooled and quenched by addition of methanol (30 ml). The reaction mixture was then concentrated in vacuo and the colourless residue cautiously suspended in 4N HCl (aq) (400 ml) before refluxing for 2.5 hours. The reaction mixture was cooled and dichloromethane (200 ml) added. Layers were separated and the aqueous layer rendered basic by addition of potassium carbonate before re-extracting with dichloromethane (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a colourless oil (12.51 g, 0.05 mol, 84%). 1H NMR (CDCl3, 400 MHz) δ: 0.95 (t, 3H), 1.59 (q, 2H), 2.05 (t, 1H), 2.23 (t, 1H), 2.40 (t, 2H), 2.81 (d,1H), 2.98 (d1H), 3.80 (s, 3H), 3.85 (t, 1H), 4.05 (d, 1H), 4.60 (d, 1H), 6.81 (d, 1H), 6.91 (d, 1H), 7.21 (t, 1H), 7.23 (s, 1H). LRMS: m/z 236. Analysis found C, 68.94; H, 8.80; N, 5.79%. C14H21NO2.0.5H2O requires C, 68.82; H, 9.08; N, 5.73%.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([O:4][C:5]([C@H:7]([NH:25][C@H:26]([C:31](O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])=[O:6])[CH3:3].OC1C2N=NNC=2C=CC=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][NH2:52])[CH:46]=1.C1(N=C=NC2CCCCC2)CCCCC1>O.CN(C=O)C>[CH3:1][C:2]([O:4][C:5](=[O:6])[C@H:7]([NH:25][C@H:26]([C:31]([NH:52][CH2:51][C:47]1[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:34])[CH3:3]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1cccnc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
100 mg of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)propyl]-L-leucine, prepared as in Example L, was added to 2.5 mL of DMF. 39.2 mg of hydroxybenzotriazol.H2O was added to the mixture followed by 0.026 mL of (pyridin-3-ylmethyl)amine. The mixture was cooled to 0° C. and 52.8 mg dicyclohexylcarbodiimide was added. The mixture was warmed to 23° C. and stirred for 24 h. The solvents were removed by evaporation and the resultant residue was diluted with ethyl acetate. The mixture was extracted with a saturated solution of sodium bicarbonate and the organic layer was separated, dried (MgSO4), and filtered. The solvent was removed by evaporation to afford the title compound; 139 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[C:15]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=2)[CH2:25][CH2:24]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: CC(=O)Nc1cc(Br)ccc1[N+](=O)[O-]
Product: CC(=O)Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Yield: 98.7 %

Procedure:
A solution of 5-bromo-2-nitrobenzenamine (0.5 g, 2.3 mmol), acetyl chloride (0.18 ml, 2.5 mmol) and potassium carbonate (0.64 g, 4.6 mmol) was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. Crude N-(5-bromo-2-nitrophenyl)acetamide (0.40 g, 70%) was obtained after removing of the solvents. A solution of N-(5-bromo-2-nitrophenyl)acetamide (0.3 g, 1.1 mmol) and benzoyl piperazine (0.44 g, 2.3 mml) was stirred at 105° C. under argon atmosphere for 16 hours. The reaction was quenched with 500 ml water and extracted with ethyl acetate (2×10 ml). N-(5-(4-benzoylpiperazin-1-yl)-2-nitrophenyl)acetamide (0.4 g, 93%) was obtained after flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.31 (s, 3H), 3.40-3.57 (m, 8H), 6.56 (dd, J=2.8, 9.7 Hz, 1H), 7.48 (m, 5H), 8.21 (d, J=9.7 Hz, 1H), 8.38 (d, J=9.7 Hz, 1H), 11.0 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 26.4, 47.1, 47.3, 61.4, 103.8, 108.5, 127.2, 127.6, 129.0, 129.1, 130.7, 135.5, 138.3, 155.7, 170.1, 171.1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([P:21](=[O:30])([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24])([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14])[F:10])[CH:5]=[N:6][CH:7]=1.[NH:31]1[C:39]2[C:34](=[CH:35][C:36](B(O)O)=[CH:37][CH:38]=2)[CH:33]=[N:32]1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[NH:31]1[C:39]2[C:34](=[CH:35][C:36]([C:2]3[CH:3]=[C:4]([CH2:8][C:9]([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:14])[CH3:15])([P:21](=[O:30])([O:22][CH:23]([CH3:25])[CH3:24])[O:26][CH:27]([CH3:29])[CH3:28])[F:10])[CH:5]=[N:6][CH:7]=3)=[CH:37][CH:38]=2)[CH:33]=[N:32]1
Reactant: CC(C)OP(=O)(OC(C)C)C(F)(Cc1cncc(Br)c1)P(=O)(OC(C)C)OC(C)C
Reactant: OB(O)c1ccc2[nH]ncc2c1
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: [K+]
Solvent: COCCOC
Product: CC(C)OP(=O)(OC(C)C)C(F)(Cc1cncc(-c2ccc3[nH]ncc3c2)c1)P(=O)(OC(C)C)OC(C)C
Temperature: 80 °C
Reaction time: 36 h
Yield: 45 %

Procedure:
Tetraisopropyl (2-(5-bromopyridin-3-yl)-1-fluoroethane-1,1-diyl)bis(phosphonate) (85 mg; 0.16 mmol), Pd(PPh3)4 (36.9 mg; 0.032 mmol) and (1H-indazol-5-yl)boronic acid (39 mg; 0.24 mmol) are added to the vial and the vial is capped with a septum. DME (4 mL) is added and the vial is flushed with argon, an aqueous solution of potassium carbonate (2.5 eq.) is added and the mixture is flushed again with argon. The reaction mixture is stirred at 80° C. for 36 h under an atmosphere of argon. The mixture was cooled to RT, diluted with EtOAc and filtered through Celite™, the Celite™ is washed three times with EtOAc/MeOH (1:1). The filtrate is deposited on silica gel and purified by column chromatography (on pre washed silica with 1% NEt3 in hexanes) using a solvent gradient from hexanes to EtOAc and then to 50% MeOH in EtOAc. The pure product is isolated as a brown oil (41 mg, 45% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:26]([CH3:32])[C:27](=[O:29])[CH3:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(NC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N(C)C(C)=O
Yield: 17.3 %

Procedure:
To a solution of N-{1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl}acetamide (72.0 mg, 0.159 mmol) in N,N-dimethylformamide (1.6 mL) was added sodium hydride (60%, 7.6 mg, 0.19 mmol). After the resultant mixture was stirred at room temperature for 30 min, methyl iodide (0.0119 mL, 0.191 mmol) was added, and the resultant mixture wad stirred at 60° C. for 2 hr. After sodium hydride (60%, 7.6 mg, 0.19 mmol) and methyl iodide (0.0119 mL, 0.191 mmol) were added again, the resultant mixture was stirred at 60° C. for 2 hr, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-90% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (12.8 mg, 0.0275 mmol, 17%).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C:11]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[BH4-].[Na+].Cl>C(O)C>[OH:10][C:11]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1cccc(C=O)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(CN[C@H](C)c2ccccc2)c1O
Yield: 98.4 %

Procedure:
15.0 g (0.124 mole) of (R)-(+)-1-phenylethylamine and 19.8 g (0.13 mole) of 2-hydroxy-3-methoxybenzaldehyde were dissolved in 300 ml of ethyl alcohol, and the resultant solution was stirred at room temperature for 3 hours, and then stirred under reflux for 2 hours. After that, 2.35 g (0.062 mole) of sodium borohydride were added at room temperature to the reaction mixture, which was then stirred at a temperature of from 30° to 35° C. for 1 hour, and thereafter stirred at a temperature of from 55° to 60° C. for 1.5 hours. After the completion of the reaction, 50 ml of a 10% hydrochloric acid were added at room temperature. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in 150 ml of water. The aqueous solution thus formed was washed with 150 ml of toluene, and the aqueous layer was neutralized or weakly alkalized with a 23% aqueous sodium hydroxide solution. The toluene layer was washed with water, and concentrated under reduced pressure to give 31.41 g of (R)-(+)-N-(2-hydroxy-3-methoxybenzyl)-1-phenylethylamine as oily substance. Yield: 98.6%.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][O:24]CC2C=CC=CC=2)[O:11][C@H:10]1[N:32]1[C:44]2[C:43]3[NH:45][C:46]4[CH:47]=[C:48]([F:53])[C:49]([F:52])=[CH:50][C:51]=4[C:42]=3[C:41]3[C:54](=[O:58])[NH:55][C:56](=[O:57])[C:40]=3[C:39]=2[C:38]2[C:33]1=[CH:34][C:35]([F:60])=[C:36]([F:59])[CH:37]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][OH:24])[O:11][C@H:10]1[N:32]1[C:44]2[C:43]3[NH:45][C:46]4[CH:47]=[C:48]([F:53])[C:49]([F:52])=[CH:50][C:51]=4[C:42]=3[C:41]3[C:54](=[O:58])[NH:55][C:56](=[O:57])[C:40]=3[C:39]=2[C:38]2[C:33]1=[CH:34][C:35]([F:60])=[C:36]([F:59])[CH:37]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](COCc2ccccc2)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: II
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](CO)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
To a solution of 12-[4-deoxy-2,3,6-tri-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (6.49 g, 7.97 mmol) in 90 mL of acetic anhydride was added solid I2 (0.406 g, 1.6 mmol) and the mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with ethyl acetate, washed (30% aq. Na2S2O3, saturated aq. NaHCO3, H2O, brine) dried (MgSO4) and evaporated. The residue was taken up in methanol (150 mL), 15 mL of concentrated NH4OH was added and the mixture was stirred at room temperature for 18 h. The mixture was then evaporated to dryness and the residue was chromatographed (SiO2/hexane-ethyl acetate, 95:5 to 1:1) to give 12-[4-deoxy-2,3,-di-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (2.35 g, 41%) and then 12-[4 deoxy-2-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (2.40 g, 48%), both as yellow solids.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[C:20]1([CH3:29])[C:21]([C:26](Cl)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:26](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH3:29]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1C
Yield: 44.5 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and o-toloyl chloride (Aldrich, 0.22 g, 1.4 mmol) in 15 mL THF were processed using the method described in Example 129 to afford the title compound (0.15 g, 0.49 mmol, 46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.23 (d, J=0.7 Hz, 3H), 2.26 (s, 3H), 2.70 (s, 3H), 3.31 (s, 3H), 3.77 (t, J=5.3 Hz, 2H), 4.35 (t, J=5.3 Hz, 2H), 7.23 (t, J=7.5 Hz, 2H), 7.27-7.35 (m, 1H), 8.08-8.14 (m, 1H); MS (DCI/NH3) m/z 305 (M+H)+; Anal. calculated for C16H20N2O2S: C, 63.13; H, 6.62; N, 9.20. Found: C, 63.43; H, 6.53; N, 9.14.