Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>CN(C=O)C>[CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCCl
Reactant: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(-c2ccnc(NC3CCCCC3)n2)c2cccnc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
Compound 13 (25 mg) was dissolved in DMF (1 mL) and NaH (5 mg) was added. The mixture was stirred for 1 hr, followed by addition of 2-(dimethylamino)ethyl chloride hydrochloride (10 mg). After being warmed to 45° C. for 2 hrs, the solution was concentrated and the residue was purified by flash chromatography [silica gel, DCM:MeOH/9.5:0.5] to afford 13 mg (42%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 8.72 (d, 1 H), 8.35 (d, 1 H), 8.18 (d, 1 H), 7.92 (s, 1 H), 7.15 (dd, 1 H), 6.80 (d, 1 H), 5.01 (d, 1 H), 4.45 (t, 2 H), 3.95 (m, 1 H), 2.80 (t, 2 H), 2.32 (s, 6 H), 2.15 (m, 2 H), 1.80 (m, 2 H), 1.70 (m, 2 H), 1.45 (m, 2 H), 1.30 (m, 2 H). MS (ESI) m/z: 365 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[C:3](=[NH:7])[O:4]CC.[O:18]1CCC[CH2:19]1>C1(C)C=CC=CC=1>[F:17][C:14]([F:15])([F:16])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:2]1[O:1][C:19](=[O:18])[NH:4][C:3]1=[O:7]
Reactant: CCOC(=N)C(O)c1ccccc1C(F)(F)F
Reactant: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2ccccc2C(F)(F)F)O1

Procedure:
By the procedure of Method A of Example 12, ethyl 1-hydroxy-1-(2-trifluoromethylphenyl)methanecarboximidate (10 g.) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-trifluoromethylphenyl)oxazolidine-2,4-dione (5.3 g., 54%; m.p. 91°-93° C.; m/e 245).
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[C:4](C(O)=O)[S:5][C:6]=2C(O)=O)[O:2]1>[Cu].C(O)CO>[CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[CH:4][S:5][CH:6]=2)[O:2]1
Reactant: O=C(O)c1sc(C(=O)O)c2c1OCCO2
Agent: [Cu]
Solvent: OCCO
Product: c1scc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
3,4-Ethylenedioxy-2,5-thiophenedicarboxylic acid (460 g) and a copper powder (69 g) were added to ethylene glycol (1400 g) at room temperature. The reaction mixture was stirred under air for 30 minutes at room temperature, and air was continuously introduced into the reaction mixture. The reaction mixture was then heated at 140° C. for 8 hours. After the reaction was complete, the reaction mixture was purified using the same process as described in Example 1 to obtain 3,4-ethylenedioxythiophene (281 g, purity: 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.[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>[N:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=2)=[CH:3][N:4]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Brc1ccnnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: OCc1ccc(-c2ccnnc2)cc1
Yield: 63.7 %

Procedure:
To a solution of 4-bromopyridazine (131 mg, 0.824 mmol) in 1,2-dimethoxyethane (16.4 ml) were added 4-hydroxymethylphenylboronic acid (189 mg, 1.24 mmol), potassium carbonate (517 mg, 3.74 mmol) and water (8.2 ml), which was deaerated under reduced pressure, followed by argon substitution. Tetrakis(triphenylphosphine)-palladium (73.5 mg, 0.0636 mmol) was then added, followed by heating to reflux for 5 hours under argon atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was subjected to reversed phase column chromatography (column; Megabond Elut™ C18 (manufactured by Varian, Inc.), eluent; acetonitrile:water=0:1→1:4 (VAT), then methanol), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (97.7 mg) as a slightly brown solid. (Yield: 64%)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15](NC)=[O:16])(=[O:13])=[O:12]>ClC1C=CC=CC=1>[F:20][C:2]([F:1])([F:19])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12]
Reactant: CNC(=O)NS(=O)(=O)c1ccccc1CCC(F)(F)F
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1ccccc1CCC(F)(F)F

Procedure:
40.3 g of N-[2-(3,3,3-trifluoropropyl)-phenylsulfonyl]-N'-methylurea are suspended in 700 ml of chlorobenzene, and dried by the azeotropic distilling off of about 150 ml of solvent. There are then introduced at 120°-130° C. 71 g of phosgene in the course of 90 minutes. The yield after complete concentration of the formed solution by evaporation is 37.3 g of 2-(3,3,3-trifluoropropyl)-phenylsulfonylisocyanate in the form of yellowish oil, which can be directly further reacted.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:23]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:24])[CH2:10][N:9]=2)=[C:18](I)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2].C([Mg]Cl)(C)C.[C:30]1(=[O:34])[CH2:33][CH2:32][CH2:31]1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:23]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:24])[CH2:10][N:9]=2)=[C:18]([C:30]2([OH:34])[CH2:33][CH2:32][CH2:31]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2]
Reactant: O=C1CCC1
Reactant: CCc1cn(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C4(O)CCC4)C3=C2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
113-1. A solution of 2-(4-ethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (250 mg, 0.58 mmol) in dry THF was cooled to −78° C. under Ar and a solution of iPrMgCl*LiCl (1.78 mL, 2.31 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and cyclobutanone (0.22 mL, 2.90 mmol) was then added dropwise. The mixture was stirred at −78° C. for another 30 min and then at RT for 4 h. The mixture was poured onto a saturated aq. solution of NH4Cl and the mixture was extracted with AcOEt. The combined org. phases were then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 9:1) gave the title compound (129 mg) as a red solid. UPLC-MS: MS 377.3 (M+H+); UPLC rt 0.76 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-])=O>C(O)C>[CH3:10][C:5]1[C:4]([NH:1][NH:1][C:4]2[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1ccccc1NNc1ccccc1C
Yield: 48 %

Procedure:
The identical reduction of o-nitrotoluene as described in Example 3 was performed only the ethanol was eliminated. This reduction resulted in the isolation of a 48% yield of o-hydrazotoluene. Although the o-hydrazotoluene has a good solubility in tetrahydrofuran, the absence of ethanol prohibits the necessary level of sodium hydroxide from being dissolved in the reactive phase.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([CH3:25])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[C:18]([CH3:25])=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.6 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (2.40 g), 2,6-dimethyl-4-nitrophenol (1.50 g) and triphenylphosphine (3.06 g) in dichloromethane (60 ml) was added dropwise diethyl azodicarboxylate (1.80 ml) in an ice bath and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=5/1 as an eluant to give the desired compound (2.25 g, yield 71%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21](NC(C)C)([CH3:23])[CH3:22].C(Br)C=C.C(OCC)(=O)C>C(#N)C>[CH2:23]([O:15][C:14]([C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=1)[O:10][C:8]([CH3:20])([CH3:9])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH:21]=[CH2:22]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(C(=O)O)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: C=CCOC(=O)c1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-(1-tert-Butoxycarbonyl-1-methylethoxy)benzoic acid (14.92 g, 53.22 mmol) was dissolved in acetonitrile (60 mL). Subsequently, diisopropylamine (8.25 g, 63.87 mmol) was added thereto. Thereafter, allyl bromide (12.87 g, 106.45 mmol) was added dropwise, and the mixture was stirred for five hours at room temperature. Ethyl acetate was added for extraction. Washing was performed sequentially with water and saturated brine, followed by drying over magnesium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=10/1), whereby a colorless oil was obtained (11.59 g, 36.19 mmol, 67.9%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:15])=[C:9]([CH2:12][CH:13]=[CH2:14])[CH:10]=2)[CH2:5][C:4]1=[O:16])[CH3:2].C([O-])(=O)C.[OH-].[Na+].[BH4-].[Na+]>C(OCC)C.O.O1CCCC1>[CH3:14][CH:13]1[O:15][C:8]2=[CH:7][C:6]3[CH2:5][C:4](=[O:16])[N:3]([CH2:1][CH3:2])[C:11]=3[CH:10]=[C:9]2[CH2:12]1
Reactant: C=CCc1cc2c(cc1O)CC(=O)N2CC
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)Cc2cc3c(cc21)CC(C)O3
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 6.0 g. (27.6 mmoles) of 1-ethyl-5-hydroxy-6-allyloxindole in 105 ml. of tetrahydrofuran was added 8.79 g. (27.6 mmoles) of mecuric acetate, and the reaction stirred for 1.5 hours. The mixture was diluted with 29 ml. of 3N sodium hydroxide solution followed by the addition of 522 mg. (13.7 mmoles) of sodium borohydride in 29 ml. of 3N sodium hydroxide solution. The mixture was stirred for 1 hour and was then diluted with diethyl ether and water. The organic phase was washed with water and a saturated brine solution, and then dried over magnesium sulfate. Evaporation of the solvent and chromatographing of the residue on 100 g. of silica gel, using diethyl ether-hexane (1:1, v:v) as the eluent, gave 1.68 g. (28% yield) of the desired product.
Reaction SMILES: [CH2:1]([C:11]1[C:18]2[S:17][C:16]3[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:20](C(O)=O)[S:21][C:15]=3[C:14]=2[S:13][C:12]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>[Cu].CCCCCC>[CH2:1]([C:11]1[C:18]2[S:17][C:16]3[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][S:21][C:15]=3[C:14]=2[S:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1c(C(=O)O)sc2c1sc1c(CCCCCCCCCC)c(C(=O)O)sc12
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CCCCCCCCCCc1csc2c1sc1c(CCCCCCCCCC)csc12
Temperature: 255 °C
Yield: 44.6 %

Procedure:
Compound 68 (8.6 g, 0.016 mol), copper powder (0.7 g) and quinoline (50 mL) are combined and heated at 250-260° C. in a Woods metal bath. When no further bubbles of carbon dioxide gas could be detected (about 2 hours), the mixture is cooled to room temperature and hexane (200 mL) is added. This mixture is washed repeatedly with HCl (1-2 M in water) to remove quinoline. The organic layer is dried over MgSO4 and concentrated by evaporation, and the residue is purified by column chromatography (SiO2/hexanes) to yield compound 63 (3.4 g, 47.4%). 1H NMR (CD2Cl2): δ 6.97 (s, 2H), 2.73 (t, 4H), 1.78 (m, 4H), 1.27 (m, 28H), 0.88 (t, 6H). 13C NMR: 141.89, 136.75, 130.99, 120.57, 32.33, 30.02, 29.79 (m, overlap), 29.74, 29.15, 23.10, 14.28.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH:7]2[O:11][CH:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][CH:9]3[CH:8]2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][O:3]1>CO.C(O)(=O)C.O>[CH3:15][C:13]1([CH3:16])[O:12][C@@H:10]2[C@@H:9]([C@@H:8]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:7]([C@H:5]([OH:6])[CH2:4][OH:3])[O:11]2)[O:14]1
Reactant: CC1(C)OCC(C2OC3OC(C)(C)OC3C2OCc2ccccc2)O1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC1(C)O[C@H]2O[C@H]([C@H](O)CO)[C@H](OCc3ccccc3)[C@H]2O1
Reaction time: 16 h
Yield: 77.1 %

Procedure:
Crude 3-O-benzyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (6) (23.5 g, 75.6 mmol) was dissolved in a 1:1:1 mixture of methanol, acetic acid and water (200 ml) and stood at 50° C. for 16 hours. The solvents were evaporated and the crude syrup purified by flash chromatography (ethyl acetate-hexane 3:2) to give 3-O-benzyl-1,2-O-isopropylidene-α-D-glucofuranose (18.1 g, 87%) as a clear oil, [α]20D -49.9° (c, 1.08 in chloroform) [lit.44 -50.8° (c, 1.24 in chloroform)]; 1H NMR δ 1.33, 1.49 (6H, 2×s, acetonide); 2.17 (2H, bs, 2×OH); 3.69, 3.81 (2H, 2×dd, H-6,6', J6,6' 11.4 Hz, J5,6 5.5 Hz, J5,6' 3.4 Hz); 4.00-4.15 (3H, m, H-3, H-4, H-5); 4.56, 4.73 (2H, 2×d, CH2Ph, JH,H' 11.7 Hz); 4.63 (1H, d, H-2); 5.94 (1H, d, 1-H,J1,2 3.7 Hz); 7.31-7.38 (5H, m, H-Ph).
Reaction SMILES: O1CCCC1.[CH3:6][O:7][CH2:8][O:9][C:10]1[C:11]([CH3:35])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([C:22](OCC)=[O:23])[CH2:14][CH2:13]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C(OCC)(=O)C>[CH3:6][O:7][CH2:8][O:9][C:10]1[C:11]([CH3:35])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:22][OH:23])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:14][CH2:13]2
Reactant: CCCCCCCCC1(C(=O)OCC)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCC1(CO)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10 ml of tetrahydrofuran containing 3.3 g of ethyl 6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-carboxylate (prepared as described in Preparation 12) were added dropwise to a mixture of 0.45 g of lithium aluminum hydride and 30 ml of tetrahydrofuran under a nitrogen stream, and whilst ice-cooling. The resulting mixture was stirred for 3 hours at room temperature. Ethyl acetate and 5% w/v aqueous hydrochloric acid were then added to the reaction mixture, whilst ice-cooling, and the organic layer was separated. Then the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give the title compound.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Sb](F)(F)[F:19].C>C1(C)C(C)=CC=CC=1.CO>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([F:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: F[Sb](F)F
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: O=C(F)N(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
DPFC was prepared according to a published method of Metzger and Wilson (Biochem., 1964, Vol. 3, pp 926-931). Diphenylcarbamyl Chloride was obtained from Aldrich Chemical Co. Inc., Milwaukee, Wis., USA. DFPC was prepared from the chloride by reaction with 50% excess antimony trifluoride in hot xylene for one hour. The mixture was cooled to room temperature. Antimony halides were then precipitated with ether and the solution decolorized with charcoal, filtered and evaporated to dryness. The solids thus obtained were dissolved in Methanol, decolorized with charcoal, filtered and crystalized by cooling the solution to about 0° C. This process was repeated again and yielded white crystals with melting point of 81°-82° C.
Reaction SMILES: Br[C:2]1[O:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.C([Li])(C)(C)C.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>O1CCCC1>[CH3:14][Si:15]([CH3:17])([CH3:16])[C:2]1[O:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: O=Cc1coc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C=O)co1

Procedure:
To a stirred solution of 5-bromo-3-furaldehyde, dimethyl acetal (1.26 g., 5.7 mmol) in 10 ml dry tetrahydrofuran at 78° under argon was added t-butyllithium (9.69 mmol in pentane), followed by the subsequent addition of trimethylsilyl chloride (1.36 g., 12.54 mmol). After two hours the reaction was quenched with a 10% ammonium chloride solution and the organic portion was washed with 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. Purification by flash chromatography (10% ether/pet. ether) yielded the desired aldehyde.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:18][CH:17]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Nc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cnc(-c2ccc(Cl)cc2)cn1
Temperature: 110 °C

Procedure:
Under an argon atmosphere 50 mL 2 M Na2CO3 solution and 1.2 g (1.0 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 8.7 g (50.0 mmol) 5-bromo-pyrazin-2-ylamine and 8.0 g (50.0 mmol) 4-chlorophenyl-boric acid in 150 mL 1,4-dioxane and 50 mL MeOH and the reaction mixture is heated to 110° C. for 2.5 h. The mixture is evaporated down i.vac., the residue is combined with water, extracted exhaustively with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient: DCM to DCM/MeOH 20:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=O)[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([N:34]([CH2:43][CH3:44])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1)[CH3:33].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:43]([N:34]([CH2:32][CH3:33])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:25]([C:23]2[CH:24]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=3)[C:16](=[O:31])[N:17]3[C:22]=2[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[O:27])=[CH:37][CH:36]=1)[CH3:44]
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Reactant: CCN(CC)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCN(CC)c1ccc(CNC(=O)c2cc(-c3ccc(OCc4ccccc4)cc3)c(=O)n3ccc4ccsc4c23)cc1

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with 4-diethylamino-benzylamine, N-methylmorpholine, 1-hydroxybenzotriazole and N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride in dimethylformamide.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:23]=[CH:22][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)O1.Br[C:26]1[N:31]2[N:32]=[C:33]([NH2:35])[N:34]=[C:30]2[CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O>[O:21]=[S:17]1(=[O:20])[CH2:16][CH2:15][N:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([C:26]3[N:31]4[N:32]=[C:33]([NH2:35])[N:34]=[C:30]4[CH:29]=[CH:28][CH:27]=3)=[CH:23][CH:22]=2)[CH2:19][CH2:18]1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: CC1(C)OB(c2ccc(CN3CCS(=O)(=O)CC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Temperature: 90 °C

Procedure:
4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) was added to a solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhydrous MgSO4 and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:31]([O:34][CH2:35]OC)(=O)C>CCCCCC>[C:1]([O:7][CH2:8][CH:9]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[O:10][CH2:31][O:34][CH3:35])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COCOC(C)=O
Reactant: CC(C)(C)C(=O)OCC(O)COC(=O)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCC
Product: COCOC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
50.45 g of 1,3-dipivaloyl glycerol was dissolved in 200 ml of methoxymethyl acetate. After the addition of 2.5 g of p-toluenesulfonic acid monohydrate, the mixture was stirred for 1 hr then diluted with 200 ml of hexane and washed twice with 200 ml saturated aqueous sodium carbonate, once with aqueous NaCl solutions, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 1,3-dipivaloyl-2-methoxymethyl glycerol as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=O)[O:8][C:7](=[O:12])[C:6]=2[C:13]=1[OH:14]>CO>[NH2:10][C:5]1[C:6]([C:7]([O:8][CH3:9])=[O:12])=[C:13]([OH:14])[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=c1[nH]c2ccc(Br)c(O)c2c(=O)o1
Solvent: CO
Product: COC(=O)c1c(N)ccc(Br)c1O
Yield: 23 %

Procedure:
A mixture of Example 385C (˜18 g) in methanol (400 mL) was heated to reflux for 2 hours and then purified on a silica gel column with 20% ethyl acetate in hexanes to provide the desired product (3.95 g, 29.8% yield for three steps). 1H NMR (DMSO-d6) δ 3.90 (s, 3H), 6.22 (d, 1H), 6.60 (s, 2H), 7.30 (d, 1H), 11.70 (s, 1H); MS (DCI/NH3) m/e 246, 248 (M+H)+.
Reaction SMILES: [Na+].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:12][C:13]([CH3:16])([CH3:15])[CH2:14][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:11])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(C)(C)CBr
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CC(C)(C)C)cc1
Yield: 45.4 %

Procedure:
In a sealed tube, dissolve p-toluenesulfinic acid sodium salt (5.71 g, 32.1 mmol) in DMF (20 mL) and water (10 mL). Add neo-pentyl bromide (6.3 mL, 48 mmol) and tetrabutylammonium iodide (592 mg, 1.60 mmol) and heat the mixture at 145° C. overnight. Cool the reaction to ambient temperature, dilute with water and extract 3 times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (3.3 g, 45%).