Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH:15]1[CH2:18][NH:17][CH2:16]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:15]1[CH2:18][N:17]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CNC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CN(S(=O)(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of azetidin-3-yl-benzyl-carbamic acid tert-butyl ester (0.20 g, 0.76 mmol) in dichloromethane (2 ml) was added triethylamine (0.15 g, 1.5 mmol) followed by 4-fluorobenzenesulfonyl chloride (0.17 g, 0.84 mmol). The mixture was stirred at room temperature for 18 h. It was then quenched with 50% sodium carbonate solution and the volatiles were evaporated. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and evaporated. The crude material was washed with hexanes to give 0.29 g of a colorless gum; MS (ES) m/z 420.9 (MH+); HRMS (FAB) Calcd. for C21H26FN2O4S (MH+): 421.1597, Found: 421.1633.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[C:22]([CH2:34][CH:35]=[C:36]([CH3:39])[CH2:37]O)=[C:23]([O:32][CH3:33])[C:24]([CH3:31])=[C:25]2[C:29]=1[C:28](=[O:30])[O:27][CH2:26]2.C(Br)(Br)(Br)[Br:41]>ClCCl>[Br:41][CH2:37][C:36]([CH3:39])=[CH:35][CH2:34][C:22]1[C:21]([OH:20])=[C:29]2[C:25]([CH2:26][O:27][C:28]2=[O:30])=[C:24]([CH3:31])[C:23]=1[O:32][CH3:33]
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CO)C(=O)OC2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1CC=C(C)CBr)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked in dichloromethane (10 mL) for 1 hour 7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) were added sequentially and the mixture was shaken for 1 hour at room temperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added and the mixture was shaken further for 1 hour The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0% to 60% ethyl acetate/hexanes) to afford 6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one as an oil (52 mg, 42%); 1H NMR (300 MHz, CDCl3) δ 1.95 (s, 3H), 2.16 (s, 3H), 3.44 (d, J=7.2, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68 (t, J=7.2 Hz, 1H), 7.71 (brs, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=O)=[CH:6]2.[CH3:15][C:16]([OH:25])([CH3:24])[CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][C:16]([CH3:24])([OH:25])[CH3:15])[CH2:19][CH2:20]1)=[O:14])=[CH:6]2
Reactant: CC(C)(O)CC1CCNCC1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(C(=O)N3CCC(CC(C)(C)O)CC3)cc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
To a solution of 478 mg of 5-methoxyindole-2-carboxylic acid and 432 mg of 2-methyl-1-(piperidin-4-yl)-2-propanol in 8 mL of DMF were added 575 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 169 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.2M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.2M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-24:1], and then crystallized from a mixture of ethyl acetate/diisopropyl ether to obtain 683 mg of 1-{1-[(5-methoxy-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol as a white crystal.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:13][NH2:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.F[C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[CH3:2][C:3]1([CH2:13][NH:14][C:21]2[CH:22]=[N:23][CH:24]=[CH:16][C:17]=2[C:18]([OH:20])=[O:19])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)c1ccncc1F
Reactant: CC1(CN)CCCc2ccccc21
Agent: Cl
Product: CC1(CNc2cnccc2C(=O)O)CCCc2ccccc21
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from 1-(1-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.24 (br s, 1H), 8.31 (s, 1H), 7.78 (d, 1H, J=5.0 Hz), 7.48 (d, 1H, J=5.0 Hz), 7.45 (br s, 1H), 7.42 (d, 1H, J=7.3 Hz), 7.05-7.15 (m, 3H), 3.44-3.57 (m, 2H), 2.72 (t, 2H, J=6.4 Hz), 1.59-1.92 (m, 4H), 1.32 (s, 3H). [M+H] calc'd for C18H20N2O2, 297; found 297.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].C(O)=O.[CH3:15][NH:16][NH2:17]>C(OC)(C)(C)C>[F:1][CH:2]([F:11])[C:3]1[CH:4]=[C:5]([OH:6])[N:16]([CH3:15])[N:17]=1
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CNN
Solvent: COC(C)(C)C
Solvent: O=CO
Product: Cn1nc(C(F)F)cc1O
Temperature: 5 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
166 g (1 mol) of ethyl 4,4-difluoro-3-oxobutanoate were charged in 500 ml of methyl tert-butyl ether and treated with 140 g of formic acid. After cooling of the mixture to 5° C., 119 g (as 40% aqueous solution) of monomethylhydrazine were added. The mixture was then stirred for 20 h at 22° C. The phases were separated, and the organic phase was washed with 200 ml of water and dried over MgSO4. After the removal of the solvent under reduced pressure, 148 g of the product was obtained as an yellow solid having an m.p. of 133° C. and a purity of 95%. Yield 95%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].FC1C=CC([B:23]([OH:25])[OH:24])=C(O[C@H](CC=C)C)C=1>>[CH3:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([B:23]([OH:25])[OH:24])=[C:3]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:4]=1
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Reactant: C=CC[C@H](C)Oc1cc(C)c(C)cc1Br
Product: C=CC[C@H](C)Oc1cc(C)c(C)cc1B(O)O
Yield: 85 %

Procedure:
Prepared in 85% yield from (S)-1-bromo-4,5-dimethyl-2-(pent-4-en-2-yloxy)benzene following the procedure for (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid. 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 6.72 (s, 1H), 5.93-5.82 (m, 1H), 5.81 (d, J=5.8 Hz, 2H), 5.22-5.13 (m, 2H), 4.68-4.55 (m, 1H), 2.60-2.42 (m, 2H), 2.28 (s, 3H), 2.22 (s, 3H), 1.38 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(Cl)(=O)C.[CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH2:10]>>[C:1]([O:4][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: C=COCCCC
Solvent: CC(=O)Cl
Product: CCCCOC(C)OC(C)=O
Reaction time: 1.5 h

Procedure:
Into a 2000 ml reaction flask, equipped with stirrer, cooling bath, thermometer, addition funnel and nitrogen blanket apparatus, is added 420 ml of acetic acid (7.0 moles) and 3.0 ml of acetyl chloride. Dropwise over a period of 1.5 hours, while maintaining the reaction mass at 50°-72° C. is added 950 ml (7.7 moles) of n-butyl vinyl ether (770 grams). At the end of the addition of said n-butyl vinyl ether, the reaction mass is stirred for a period of six hours, while maintaining the temperature thereof at 30° C.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>CC(N=NC(C#N)(C)C)(C#N)C>[CH3:17][Si:16]([CH3:19])([CH3:18])/[CH:14]=[CH:15]/[Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#C[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Temperature: 80 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
Tributyltin hydride (2.0 mL, 7.3 mmol, 1.0 equiv) and ethynyltrimethylsilane (2.1 mL, 15 mmol, 2.0 equiv) were combined, AIBN (60 mg, 0.36 mmol, 0.05 equiv) was added, and the resulting colorless neat solution was heated to 80° C. Upon heating, the reaction exothermed to −110° C. The reaction mixture was cooled back to 80° C. and stirred for 20 h. The reaction mixture was cooled to 23° C. to afford the crude title compound as a pale yellow oil (2.8 g, 99% crude yield): 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=22.5 Hz, 1H), 6.60 (d, J=22.5 Hz, 1H), 1.44-1.54 (m, 6H), 1.23-1.35 (m, 6H), 0.82-0.91 (m, 15H), 0.03 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)[CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([N:33]2[CH2:34][CH:35]=[C:30]([C:26]3[CH:25]=[C:24]([C:23]([F:37])([F:22])[F:36])[CH:29]=[CH:28][N:27]=3)[CH2:31][CH2:32]2)=[O:16])[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccnc(C2=CCNCC2)c1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.288 g, 1.06 mmol) and 4-(trifluoromethyl)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine dihydrochloride (0.320 g, 1.06 mmol) in dry methylene chloride (11.5 mL) was added triethylamine (0.592 mL, 4.25 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phospsphonium hexafluorophosphate (0.517 g, 1.17 mmol). After being stirred at room temperature overnight, the brown reaction mixture was washed with NaHCO3 and brine, dried (MgSO4), filtered, and concentrated The residue was purified by column chromatography on silica gel (30:70 EtOAc/hexanes) to provide a light yellow solid product: 265 mg (52%). LC-MS calculated for C25H34F3N3O3: (M+H) 482; found 382.2 (M-Boc+1).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[NH:12][C:13](=[O:22])[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:26][C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1>CN(C=O)C>[CH3:32][N:30]1[N:29]=[N:28][C:27]([CH2:26][O:22][C:13]2[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:10]3[N:11]([C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][N:9]=3)[N:12]=2)=[N:31]1
Reactant: O=c1[nH]n2c(-c3ccccc3)nnc2cc1-c1ccccc1
Reactant: Cn1nnc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc(COc2nn3c(-c4ccccc4)nnc3cc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
To the product from Example 73, Step a (0.15 g, 0.52 mmol) in anhydrous DMF (5 ml) was added sodium hydride (60% dispersion in oil, 31.2 mg, 0.780 mmol) and the mixture was stirred under nitrogen at room temperature for 45 min then at 80° C. for another 20 min. After allowing to cool, a solution of 5-chloromethyl-2-methyl-2H-tetrazole (Moderhack, D., Chem. Ber., 1975, 108, 887-896) (0.103 g, 0.780 mmol) in anhydrous DMF (4 ml) was added and the mixture was stirred at room temperature under nitrogen for 1.5 h, then at 80° C. for 17 h. The mixture was then partitioned between water (30 ml) and ethyl acetate (40 ml). The aqueous layer was further extracted with ethyl acetate (9×40 ml) and the combined organic extracts were dried (MgSO4), and evaporated in vacuo. The residue was recrystallised from EtOAc—CH2Cl2—MeOH to afford 0.1002 g (50%) of the title compound as a white solid: mp 228-233° C.; 1H NMR (360 MHz, CDCl3) δ 4.36 (3H, s), 5.79 (2H, s), 7.47-7.60 (8H, m), 8.07 (1H, s), 8.48 (2H, m); MS (ES+) m/e 385 [MH]+. Anal. Found C, 62.01; H, 4.13; N, 28.92. C20H16N8O. 0.17H2O requires C, 62.00; H, 4.25; N, 28.92%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:14][OH:15])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: NO
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(C=NO)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.5 %

Procedure:
In a mixture of ethanol (20 mL) and water (10 mL), 4-fluoro-3-nitrobenzaldehyde (2 g), hydroxylamine hydrochloride (1.07 g) and sodium acetate (1.45 g) were dissolved, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-fluoro-5-hydroxyiminomethylnitrobenzene (1.95 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:11]2[O:12]CC(C)(C)N=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[O:27]C1C(CC2C=CC=CC=2)=C(C2OCC(C)(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:11]([OH:12])=[O:27]
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(Cc2ccccc2)c1OC
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(CCc2ccccc2)c1OC
Product: COc1ccc(C(=O)O)c(CCc2ccccc2)c1OC

Procedure:
Similarly prepared from the corresponding product of step (a) or (b) were:-
Reaction SMILES: C([O:8][C@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[CH2:12][O:11][C@H:10]1[N:31]1[CH:38]=[C:37]([F:39])[C:35](=O)[NH:34][C:32]1=[O:33])C1C=CC=CC=1.B(Cl)(Cl)Cl.C(Cl)Cl.C[OH:48]>C(Cl)Cl.O>[C@@H:10]1([N:31]2[C:38](=[O:48])[C:37]([F:39])=[CH:35][NH:34][C:32]2=[O:33])[O:11][CH2:12][C@H:13]([OH:23])[C@H:14]([OH:15])[C@@H:9]1[OH:8]
Reactant: CO
Reactant: O=c1[nH]c(=O)n([C@@H]2OC[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1F
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]cc(F)c(=O)n1[C@@H]1OC[C@H](O)[C@H](O)[C@@H]1O
Temperature: -78 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
To a solution of 17 (from Part D) (2.42 g, 4.54 mmol) in CH2Cl2 (100 ml), at -78° C. under nitrogen atmosphere, 1M solution of BCl3 (50 ml, 49.94 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for 4 h and 1:1 mixture of CH2Cl2 /MeOH (100 ml) was added and the reaction mixture was brought to room temperature and the solvents were evaporated to dryness. The residue was coevaporated with MeOH (50 ml) 5 times. The residue obtained was dissolved in water and washed with CHCl3 (50×2) and CCl4 (50 ml). The water layer was evaporated to give a white solid and which was crystallized from EtOH/ether to give the pure 18 (0.94 g, 79.4%) as white crystals: mp 231° C. dec.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](Cl)=[O:6])[CH3:3].[CH3:8][O:9][C:10]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[C:51]([O:57][CH3:58])[C:11]=1[CH:12]=[CH:13][CH:14]([S:24]([CH:27]([CH:37]=[CH:38][C:39]1[C:44]([O:45][CH3:46])=[CH:43][C:42]([O:47][CH3:48])=[CH:41][C:40]=1[O:49][CH3:50])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH2:36])[CH:29]=1)(=[O:26])=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1>O1CCCC1>[CH3:58][O:57][C:51]1[CH:52]=[C:53]([O:55][CH3:56])[CH:54]=[C:10]([O:9][CH3:8])[C:11]=1/[CH:12]=[CH:13]/[CH:14]([S:24]([CH:27](/[CH:37]=[CH:38]/[C:39]1[C:40]([O:49][CH3:50])=[CH:41][C:42]([O:47][CH3:48])=[CH:43][C:44]=1[O:45][CH3:46])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH:36][C:5](=[O:6])[CH2:4][N:2]([CH3:3])[CH3:1])[CH:29]=1)(=[O:26])=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:5](=[O:6])[CH2:4][N:2]([CH3:3])[CH3:1])[CH:16]=1
Reactant: CN(C)CC(=O)Cl
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)CN(C)C)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)CN(C)C)c2)c(OC)c1
Reaction time: 8 h

Procedure:
To a solution of dimethylaminoacetyl chloride (10 mmol) in tetrahydrofuran (40 mL) is added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution is stirred overnight and the reaction progress is monitored by TLC. The solvent is removed and the residue is taken up in dichloromethane and washed with water. The organic layer is dried over anhydrous sodium sulfate and evaporated to give the desired amide product.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9](C(OC(C)(C)C)=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[OH:33][C:27]([C:29]([F:32])([F:31])[F:30])=[O:28].[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2c(-c3ccccc3)cn(C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(-c3ccccc3)c[nH]c2c1
Reaction time: 3 h

Procedure:
To a solution of 1-tert-butyl 6-methyl 3-phenyl-1H-indole-1,6-dicarboxylate 62b (4.04 mmol, 1.42 g) in CH2Cl2 (8 mL) was added 6 mL of TFA. The resulting solution was stirred for 3 h. The mixture was then concentrated and washed with hexanes to afford 62c.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].COC1C=CC(/C=[C:31]2/[C:32]([NH:34][C:35]([S:37]/2)=[NH:36])=[O:33])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH2:36][C:35]1[S:37]/[C:31](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][N:5]=[C:4]3[O:3][CH2:1][CH3:2])/[C:32](=[O:33])[N:34]=1
Reactant: CCOc1ncnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ncnc2ccc(/C=C3\SC(N)=NC3=O)cc12
Temperature: 25 °C

Procedure:
The suspension of 4-ethoxy-quinazoline-6-carbaldehyde (example 10b) (1 equiv.), pseudothiohydantoin (1 equiv.), and sodium acetate (4 equiv.) in acetic acid was stirred under reflux for 12 h. After cooling to room temperature, water was added. The solid was collected by filtration, washed with water and dried to 2-amino-5-[1-(4-ethoxy-quinazolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 301 (MH+) as a slight yellow solid. LC-MS m/e 256 (MH+).
Reaction SMILES: C(O[C@@H:5]1[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:16]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][C:21](=[O:23])[CH3:22])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C[Si]([N:52]=[N+:53]=[N-:54])(C)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[C:21]([O:20][C@@H:19]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[O:35][C@@H:18]1[O:17][C@@H:16]1[C@@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:42][C@@H:5]([N:52]=[N+:53]=[N-:54])[C@H:6]([O:7][C:8](=[O:10])[CH3:9])[C@H:11]1[O:12][C:13](=[O:15])[CH3:14])(=[O:23])[CH3:22]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A mixture of β-lactose octaacetate (203 mg, 0.3 mmol), trimethylsilyl azide (41 mg, 0.35 mmol), and SnCl4 (40 mg, 0.15 mmol) in CH2Cl2 (1.5 ml) was stirred overnight at room temperature. The solution was diluted with CH2Cl2 (20 ml) and washed twice with 1 M potassium fluoride solution (5 ml), water (5 ml) and evaporated affording 4-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-2,3,6-tri-O-acetyl-β-D-glucopyranosyl azide (25) (178 mg 90%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:9]([SH:12])[CH2:10][CH3:11]>>[CH2:7]([O:6][C:1](=[O:5])[CH2:2][CH:3]([S:12][CH2:9][CH2:10][CH3:11])[CH3:4])[CH3:8]
Reactant: CCCS
Reactant: C/C=C/C(=O)OCC
Product: CCCSC(C)CC(=O)OCC
Temperature: 30 °C

Procedure:
Into a 500 ml one neck flask equipped with reflux condenser, spin bar, and hot plate containing a built in magnetic stirrer, cooling bath and ultra-violet light source are placed 17.9 grams (0.157 moles) of ethyl crotonate and 12 grams (0.158 moles) of n-propyl mercaptan with stirring and maintaining the temperature at 30° C., the reaction mass is stirred after turning the ultra-violet light on. The reaction mass is continued to be stirred for a period of 8 hours. At the end of the 8 hour period, the ultra-violet light was turned off and the reaction mass is transferred to a distillation flask and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[C:13]1[N:14]=[C:15]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:16]2[S:21][C:20]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)=[CH:19][C:17]=2[N:18]=1>CN(C=O)C.O>[N:1]1([C:13]2[N:14]=[C:15]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:24][CH2:25][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]4)=[CH:19][C:17]=3[N:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(Cc2cc3nc(-n4ncc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
A solution of indazole (0.118 g) in DMF (8 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 15 min, [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added and the reaction vessel sealed and heated at 150° C. After 1 h the reaction mixture was cooled to room temperature then diluted with water. The resulting precipitate was collected by filtration then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish 116 (0.233 g, 49%) as a white solid after trituration with ethyl acetate. MS m/e 478 [M+H]−; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (dd, J=11.68, 3.39 Hz, 2 H) 1.73 (d, J=10.93 Hz, 2 H) 2.07 (t, J=10.74 Hz, 3 H) 2.17 (s, 6 H) 2.94 (d, J=11.68 Hz, 2 H) 3.75-3.90 (m, 6 H) 3.93-4.13 (m, 4 H) 7.31 (t, J=7.54 Hz, 1 H) 7.39 (s, 1 H) 7.56 (dd, J=7.91, 6.40 Hz, 1 H) 7.88 (d, J=7.91 Hz, 1 H) 8.39 (s, 1 H) 8.68 (d, J=8.67 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:18][O:19][CH2:20]Cl>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:10][CH2:18][O:19][CH3:20])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCl
Reactant: O=Cc1cccc(Br)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1c(Br)cccc1C=O
Reaction time: 0.75 h

Procedure:
To 3-bromo-2-hydroxybenzaldehyde (1.33 g, 6.6 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (0.81 g, 8 mmol) then chloromethyl methyl ether (0.56 g, 7 mmol). The mixture was stirred for 45 minutes and partitioned between CH2Cl2 and saturated NaHCO3(aq). The crude material was purified by silica gel column chromatography eluting with hexanes and ethyl acetate (5:1) to afford the titled compound.