Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.[S:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[C:19]1[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[S:37]1[C:38]([C:2]2[C:10]3[C:6](=[N:7][N:8]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)[N:9]=3)[C:5]([C:22]3[S:18][C:19]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)=[CH:20][CH:21]=3)=[CH:4][CH:3]=2)=[CH:39][CH:40]=[C:36]1[C:19]1[S:18][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2cccs2)s1
Reactant: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: c1csc(-c2ccc(-c3ccc(-c4ccc(-c5cccs5)s4)c4nn(-c5ccncc5)nc34)s2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of Intermediate A (704 mg, 2.0 mmol), 50% [2,2′-bithiophen]-5-yltributylstannane (2.50 g, 5.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol), and anhydrous dimethylformamide (20 mL) was stirred under argon and heated at 90° C. for 1 hour. TLC indicated no starting material left. Heating at 90° C. was continued for an additional 2 hours. The volatiles were removed under reduced pressure, and the crude product was purified by column chromatography using silica gel and dichloromethane/ethyl acetate (9:1) as an eluent. The obtained product was washed with ethyl acetate (50 mL) and dried in a vacuum oven to give 4,7-di([2,2′-bithiophen]-5-yl)-2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazole (Example 9) as red crystals, 150 mg (14%). 1H NMR (400 MHz, CDCl3): δ 8.88 (m, 2H, pyridine), 8.40 (m, 2H, pyridine), 8.09 (d, J=4.0 Hz, 2H, thiophene), 7.65 (s, 2H, benzotriazole), 7.31 (dd, J=3.7 and 1.1 Hz, 2H, thiophene), 7.29 (m, 2H, thiophene), 7.27 (m, 2H, thiophene), 7.08 (dd, J=5.2 and 3.7 Hz, 2H, thiophene). UV-vis spectrum (dichloromethane): λmax=478 nm. Fluorimetry (dichloromethane): λmax=584 nm.
Reaction SMILES: FC(F)(F)C([O-])=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3[CH2:20][NH:21][CH2:22][CH2:23][C:18]=3[NH2+:17][N:16]=2)=[CH:11][CH:10]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3[CH2:20][N:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:22][CH2:23][C:18]=3[NH:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: Brc1ccc(C2=N[NH2+]C3=C2CNCC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCc2[nH]nc(-c3ccc(Br)cc3)c2C1
Reaction time: 2.5 h
Yield: 50.8 %

Procedure:
To a stirred solution of 3.11 g (11.1 mmol) of 3-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium trifluoroacetate and 4.71 mL (33.5 mmol) of Et3N in DMF (55 mL) was slowly added 1.21 mL (15.6 mmol) of methanesulfonyl chloride. After 2.5 h, the solvent was removed under reduced pressure and the residue was diluted with CH2Cl2 (100 mL) and saturated NaHCO3 (100 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×30 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by column chromatography (silica, 0-5% MeOH/CH2Cl2) afforded 2.01 g (50%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): m/z calculated for C13H14BrN3O2S [M++H] 356.00, observed 356.0.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:42][CH3:43])[C:34]=2[C:38]([F:41])([F:40])[F:39])[C:29]=1[CH3:44]>C(Cl)(Cl)(Cl)Cl>[Br:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:42][CH3:43])[C:34]=2[C:38]([F:40])([F:41])[F:39])[C:29]=1[CH2:44][Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(C)c(Br)ccc2c1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(CBr)c(Br)ccc2c1C(F)(F)F
Yield: 100 %

Procedure:
N-Bromosuccinimide (21.07 g, 1.5 eq) and benzoyl peroxide (84 mg, 0.0044 eq) were added to a stirred solution of 2-bromo-6-methoxy-1-methyl-5-trifluoromethylnaphthalene (25.19 g, 78.9 mmol, prepared by the process of Example 14, Step (1) in carbon tetrachloride (300 mL) at room temperature under a dry nitrogen atmosphere. The reaction was heated to reflux for 6 hours, then cooled to ~50° C. The warm reaction mixture was filtered. The solid washed with warm carbon tetrachloride (2×30 mL). The carbon tetrachloride was removed from the filtrate to provide the light yellow solid (32.4 g, 100%), m.p. 141.5°-143° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)CCc1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCc2ccc(Cl)cc2)[nH]n1
Yield: 52.8 %

Procedure:
Hydrazine hydrate (0.300 mL, 6.18 mmol) was added to a stirring room temperature solution of 67 (0.1.7484 g, 6.18 mmol) in EtOH (6.2 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (40 min): Upon cooling, a white crystalline solid precipitated from the reaction. The solid was separated by filtration, washed with EtOH, and dried to obtain pure 68 (0.9092 g, 52.7%): 1H (CDCl3, 300 MHz): δ 12.44 (1H, broad s), 7.21 (2H, d, J=8.3 Hz), 7.08 (2H, d, J=8.1 Hz), 6.58 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.00 (2H, t, J=7.0 Hz), 2.93 (2H, t, J=7.0 Hz), 1.33 (3H, t, J=7.0 Hz) ppm. Partial 13C (CDCl3, 75 MHz): δ 139.12, 131.93, 129.67, 128.50, 106.49, 60.94, 34.72, 14.20 ppm. HPLC: 10.269 min.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([N:27]([C:32]([O:34][CH3:35])=[O:33])[C:28]([O:30][CH3:31])=[O:29])[C:17]([CH3:36])=[C:16]([Cl:37])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:37][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([N:27]([C:32]([O:34][CH3:35])=[O:33])[C:28]([O:30][CH3:31])=[O:29])[C:17]=1[CH3:36]
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)N)c1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (36 mg, 0.18 mmol), dimethyl [6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]imidodicarbonate (66 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.058 mL, 0.33 mmol) in isopropyl alcohol (0.6 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired. LCMS calculated for C24H23ClFN6O4 (M+H)+: m/z=513.1. found: 513.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([CH:9]=[S:10])=[C:6]([NH2:8])[CH3:7])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1>C(O)C.CCOCC>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH3:7])=[N:8][S:10][CH:9]=1)=[O:11])[CH3:2]
Reactant: CCOC(=O)C(C=S)=C(C)N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1csnc1C
Temperature: 25 °C

Procedure:
To a solution of 3-amino-2-thioformyl-but-2-enoic acid ethyl ester (method 52) (25.6 g, 147 mmol) in ethanol (300 mL), was added m-chloroperbenzoic acid (33.3 g, 77%, 149 mmol) in ethanol (200 mL) dropwise with stirring at room temperature. After the completion of the addition the reaction mixture was heated at 75° C. for 2 h after which the MS showed the complete disappearance of the starting material. The reaction mixture was diluted with ether (500 mL) and the ethereal solution was washed with 0.1 M NaOH solution (3×500 mL) and once with water (400 mL) dried (Na2SO4) and concentrated to get the pure product as light brown oil. Yield 23.5 g (93%). 1NMR (300 MHz) δ: 1.40 (t, 3H), 2.73 (s, 3H), 5.07 (t, 1H), 4.36 (q, 2H), 9.24 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH2:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]([C:7]([F:10])([F:8])[F:9])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:30])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(N)cc1-c1c(Cl)c(C(F)(F)F)nn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Cl)c(C(F)(F)F)nn1C
Yield: 54.5 %

Procedure:
3-(4-Chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.03 g, 0.11 mmol) was treated with 4-chlorophenyl isocyanate (0.02 g, 0.13 mmol, 1.2 equiv.) in CH2Cl2 (4.0 mL), in a similar manner as described in Example 1.102. The product was further purified via reverse phase C-18 HPLC to afford Compound 41 (0.03 g, 0.06 mmol, 56% yield) as a white solid: LCMS m/z (%)=459 (M+H35Cl, 100), 461 (M+H35Cl37Cl, 84), 463 (M+H37Cl, 10). 1H NMR (400 MHz, MeOH-d4) δ: 7.59 (dd, J=8.0, 4.0 Hz, 1H), 7.41 (dd, J=8.0, 8.0 Hz, 2H), 7.40 (dd, J=8.0, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.17 (d, J=12.0 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH:26]=[C:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: CN(C)C=O
Product: Cc1c(Cc2ccccc2)nnc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 100 °C
Yield: 76.6 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethylpyridazine (800 mg, 3.44 mmol) in 20 mL DMF is added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.3 g, 4.1 mmol), followed with potassium carbonate (1.43 g, 10.3 mmol) and Pd(PPh3)4 (397 mg, 0.344 mmol) in a round bottom flask. The vial is evacuated and flushed with nitrogen. The reaction mixture is heated to 100° C. for 16 h. The mixture is filtered through Celite and the filtrate is concentrated to afford the crude material. The mixture is purified by flash chromatography on silica gel, eluting with 3%-15% MeOH: DCM. Fractions containing the desired product are combined and concentrated to afford a brown solid (1.0 g, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([F:28])[CH:22]=1)(=[O:20])=[O:19])[CH3:17]>>[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:1][C:2]2[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)=[C:23]([F:28])[CH:22]=1)(=[O:19])=[O:20])[CH3:17]
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 10 step (ii).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:53][N:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[N:52]=[CH:53][C:54]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:55][N:56]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ncc(-c2cccc(N)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methoxy-pyrimidin-5-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.005 g of product in 20% yield: LCMS (ESI) m/z 390 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11](=[O:13])[CH:10](C(OC)=O)[C:9](=[O:18])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(#N)C>[OH:18][C:9]1[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:12][C:11](=[O:13])[CH:10]=1
Reactant: COC(=O)C1C(=O)CC(c2ccccc2)NC1=O
Solvent: CC#N
Product: O=C1C=C(O)CC(c2ccccc2)N1

Procedure:
The title compound was prepared by decarboxylation of methyl 6-phenyl-2-,4-dioxopiperidine-3-carboxylate (prepared as per Ashton et al., Heterocycles 28: (2) 1015 (1989)) by refluxing in acetonitrile (as per Toda et al., J. Antibiotics 23: (2) 173 (1980)). Removal of the solvent gave a solid (m.p. 166°-169° C.). 1H NMR (CDCl3) δ2.77 (dd, 1H), 2.90 (dd, 1H), 3.38 (s, 2H), 4.80 (dd, 1H), 6.40 (s, 1H), 7.32-7.46 (m, 5H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH2:20]([O:22][Si:23](Cl)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH3:21]>O1CCCC1>[CH3:19][O:18][C:13]([O:17][Si:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])=[C:14]([CH3:16])[CH3:15]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)OC(OC)=C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A 3-necked 2-liter flask, equipped with a mechanical stirrer, thermocouple, dry-ice condenser, and a dropping funnel, was charged with tetrahydrofuran (200 mL) and diisopropylamine (70 mL, 0.50 mol) under an argon atmosphere. The mixture was cooled to 0° and n-butyllithium (313 mL, 1.6M in hexane) was added dropwise while the temperature was maintained at about 0°. The mixture was stirred for 30 minutes, followed by dropwise addition of methyl isobutyrate (57.3 mL, 0.50 mol). Stirring was continued at 0° for an additional 30 minutes and triethoxysilyl chloride (147 mL, 0.75 mol) was added. The mixture was stirred and allowed to warm up to room temperature overnight and filtered under argon to remove the precipitated lithium salts. The solvents were evaporated and the liquid residue was distilled, first using a Vigreux column, followed by spinning band distillation. The total MPTES obtained was 113.3 g (86% yield). This was identified by 1H NMR spectroscpy, IR (infrared) and GC/MS; (gas chromatography/mass spectroscopy) b.p. 59°-60°/0.15 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][CH2:12][CH2:13][OH:14].C([O-])(O)=O.[Na+].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NCCO
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCCO)cc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 149.1 %

Procedure:
A mixture of 4-methoxybenzaldehyde (10 g, 74 mmol), 2-aminoethanol (4.9 g, 81 mmol) and NaHCO3 (9.3 g, 110 mmol) in MeOH (100 mL) was refluxed for 3 hours. The reaction mixture was cooled to 15° C. To the mixture was added portionwise NaBH4 (3.3 g, 88 mmol) at 15° C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 2-[(4-methoxybenzyl)amino]ethanol (130a, 20 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[C:13]([CH2:25][C:26](OCC)=[O:27])[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[C:13]([CH2:25][CH2:26][OH:27])[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(CCO)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-ethoxycarbonylquinoline-2-acetate (5.8 g) in tetrahydrofuran (100 ml) was added dropwise to a suspension of lithium aluminum hydride (0.455 g) in tetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour, and then water (2.5 ml) was added dropwise, and the mixture was stirred for 30 minutes. The insoluble solids were separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (1:1, v/v) gave ethyl 4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)-6,7-dimethoxyquinoline-3-carboxylate (1.75 g, 33%). This was recrystallized from ethyl acetate-hexane. Colorless prisms, mp. 150°-151° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O.P(Br)(Br)[Br:17].O>C(OCC)C>[Br:17][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccccc1C(O)c1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: Cc1ccccc1C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 133.9 %

Procedure:
To a solution of 28.1 g (140 mmol) of 5 in 150 mL of dry diethyl ether, 25.6 g (8.89 mL, 94.4 mmol) of PBr3 was added at −10° C. The resulting mixture was stirred for 12 hr at room temperature and then added to 450 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 2×150 mL of water. The combined organic extracts were washed with aqueous NaHCO3, dried over Na2SO4, and then evaporated to dryness. This procedure gave 33.0 g (89%) of the title product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[S-:13][C:14]#[N:15].[Na+].BrBr.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:14]([NH2:15])[S:13][C:7]=2[CH:6]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2nc(N)sc2c1
Reaction time: 4 h
Yield: 67.2 %

Procedure:
A solution of ethyl-4-aminobenzoate (35 g, 212 mmol) in glacial acetic acid (300 mL) was added to a stirred solution of sodium thiocyanate (69 g, 848 mmol) in acetic acid (150 mL). The mixture was cooled in an ice-water bath and a solution of bromine (12 mL, 233 mmol) in acetic acid (60 mL) was added dropwise via an addition funnel. The reaction mixture was stirred at 0° C. to RT for 4 h and then poured into water (1.5 L). Saturated sodium carbonate solution was added to neutralize the solution. Precipitated solid was filtered, washed with water and EtOAc, and dried in vacuo to obtain the title compound of this step (31.65 g, 67.2% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[C:11]([CH:12]=O)[C:10]([OH:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=3[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cc(-c2ccccc2)ccc1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(-c3ccccc3)ccc2o1

Procedure:
A mixture of 0.99 g of 1A, 0.96 g of diethyl bromomalonate and 1.25 g of anhydrous potassium carbonate in 20 ml of 2-butanone, was refluxed for 10 hours. The solvent was evaporated under reduced pressure. The residue was cooled, poured into 100 ml of water and extracted with ether. The extract was washed with cold 5% sodium hydroxide solution and water and then concentrated under reduced pressure. The residue was recrystallized from ethanol to give ethyl 5-phenylbenzofuran-2-carboxylate (1B), as white crystals, mp: 109°-110° C.
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[CH:10](=[O:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:12][CH2:11][CH:10]=[O:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: C=CC=O
Reactant: CCCCOP([O-])CC
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCC=O
Yield: 82.9 %

Procedure:
149 g (1 mol) of butyl ethylphosphonite (produced as in Example 2) and 67 g (1.2 mol) of 2-propenal in 217 g of toluene are heated to about 100° C. While stirring, 124 g of a 10% strength solution of WakoV65 in toluene are metered in. The solvent is distilled off in vacuo to obtain 171 g (78% of theory) of butyl ethyl-(2-formylethyl)phosphinate.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[NH:5][C:6]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.O.[OH-].[K+]>C(O)CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:5]([C@H:4]([CH3:22])[C:3]([OH:2])=[O:23])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:12]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](C)Nc1ncccc1NC(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 4.7 %

Procedure:
A solution of (R)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alanine methyl ester (42.5 g, 0.127 mole) in ethylene glycol (250 ml) was refluxed under nitrogen atmosphere for one hour and then cooled. Water (40 ml) and solid potassium hydroxide pellets (10.13 g, 0.181 mole) were added and the solution was refluxed for an additional two hours, filtered into ice water (1 liter) and acidified with 3N hydrochloric acid solution to give a solid which was collected by filtration and rinsed with water to give 29 g of crude title compound (76% yield). A 3.5 g portion of the solid was recrystallized twice from isopropyl alcohol/water and dried under high vacuum at 50° C. overnight to give 1.81 g of title compound, mp 225°-227° C.