Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([NH:15][CH3:16])=[N:13][NH:14][C:8]=2[N:7]([CH2:17][CH2:18]O)[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([NH:15][CH3:16])=[N:13][NH:14][C:8]=2[N:7]([CH2:17][CH2:18][Cl:23])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCO)c1=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCCl)c1=O
Yield: 94 %

Procedure:
To a suspension of 5-butyl-7-(2-hydroxyethyl)-3-methylaminopyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (2.5 g, 8.9 mM) in chloroform (30 ml) and pyridine (4 ml, 50 mM) was added thionyl chloride (3,7 ml, 50 mM) at room temperature. The solution was refluxed for 2 hours and concentrated to dryness under reduced pressure to give a syrup. The syrup was poured onto ice-water to give colorless powder. Recrystallization from DMF/methanol/water gave colorless crystals (2.5 g, 94%), m.p. 270°-272° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21].[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][N:27]=1)[CH3:24].O.C(#N)C>CN(C)C=O>[CH3:3][C:4]1([CH3:22])[N:8]([CH2:32][C:30]2[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH2:23][CH3:24])[CH:31]=2)[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21]
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=O
Reactant: CCOc1cc(CBr)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(CN2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(=O)C2(C)C)ccn1
Reaction time: 0.33 h
Yield: 56.4 %

Procedure:
0.015 g of sodium hydride is added to a solution of 0.175 g of 5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 2 ml of anhydrous dimethylformamide, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is maintained at this temperature for 30 minutes. A solution of 0.185 g of 2-ethoxy-4-(bromomethyl)pyridine in 2 ml of anhydrous dimethylformamide is added, followed by addition of ice-cold water after reaction for 10 minutes. The reaction mixture is placed on a cartridge 37 mm in diameter packed with 65 g of octadecyl-grafted 40-60 μm silica conditioned successively with the mixture (water/acetonitrile) (5/95) (v/v) and then with the mixture (water/acetonitrile) (95/5) (v/v). The elution is performed with a mixture (water/acetonitrile) (95/5) (v/v) over 20 minutes, followed by a linear gradient of from 5% to 95% acetonitrile over 60 minutes, at a flow rate of 10 ml/minute. The fractions between 700 and 760 ml are concentrated under reduced pressure. 0.145 g of 5,5-dimethyl-1-(2-ethoxypyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained, the characteristics of which product are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
A mixture of 27.4 g (125.6 mmol) of 2-bromo-5-nitrophenol, 26 g (188.4 mmol) potassium carbonate, and 250 mL DMF were stirred 15 min at room temperature. 16.4 mL (138 mmol) of benzyl bromide was added in one portion to the reaction mixture and the mixture was heated to 90° C. TLC analysis indicated complete reaction, so the reaction mixture was cooled to 5° C. in an ice/water bath, filtered and concentrated. 300 mL water was added to the reaction mixture and the black precipitate was filtered and air dried. The crude product was taken up in dichloromethane and purified over silica eluting with 35% hexanes in dichloromethane, to give 2-bromo-5-nitro-O-benzylphenol 35.5 g (115.2 mmol, 91.7%) as an ivory solid. 1H NMR (400 MHz) CDCl3 7.78 (s, 1H), 7.72 (s, 2H), 7.46-7.48 (m, 2H), 7.38-7.42 (m, 2H), 7.32-7.35 (1H), 5.23 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([SH:11])[S:10][C:6]=2[C:5]([F:12])=[CH:4][C:3]=1[F:13].[CH3:14][O:15][C:16](=[O:29])[CH2:17][N:18]([C:25](=[O:28])[CH2:26]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Ca+2].Cl>O.[I-].[K+].CS(C)=O>[CH3:14][O:15][C:16](=[O:29])[CH2:17][N:18]([C:25](=[O:28])[CH2:26][S:11][C:9]1[S:10][C:6]2[C:5]([F:12])=[CH:4][C:3]([F:13])=[C:2]([F:1])[C:7]=2[N:8]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Fc1cc(F)c2sc(S)nc2c1F
Reactant: COC(=O)CN(C(=O)CCl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CN(C(=O)CSc1nc2c(F)c(F)cc(F)c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To dimethylsulfoxide (DMSO; 6 ml) was added 4,5,7-trifluoro-2-mercaptobenzothiazole (442 mg, 2 mmol), N-chloroacetyl-N-phenylglycine methyl ester (479 mg, 2 mmol), calcium carbonate (276 mg, 2 mmol) and potassium iodide (20 mg) and the mixture was stirred at room temperature for 1 hour. The resultant reaction mixture was diluted with water, acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and then evaporated to yield a residue, which was crystallized from isopropyl ether to give N-[2-(4,5,7-trifluorobenzothiazol-2-ylthio)acetyl]-N-phenylglycine methyl ester (700 mg, 82%) as a colorless powder.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=1.[F:13][C:14]([F:21])([F:20])C1C=NNC=1>>[F:13][C:14]([F:21])([F:20])[C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=1
Reactant: O=C(O)C1(n2cc(F)cn2)CC1
Reactant: FC(F)(F)c1cn[nH]c1
Product: O=C(O)C1(n2cc(C(F)(F)F)cn2)CC1

Procedure:
The title compound was prepared by a method analogous to Intermediate 4 but using 4-(trifluoromethyl)-1H-pyrazole in Step 1. 1H NMR (400 MHz, CDCl3) δ 1.60-1.79 (m, 2H), 1.83-1.95 (m, 2H), 7.75 (s, 1H), 7.78-7.89 (m, 1H), 11.82 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].C([Li])CCC.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])(=[O:4])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C

Procedure:
Prepared in analogy to Example 44(a) from 1-(dimethylsulfamoyl)-imidazole, butyl lithium and tert-butyldimethylsilyl chloride in tetrahydrofuran to afford 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide, then treatment of this with butyl lithium and 2,6-diethyl-4-phenoxy-benzaldehyde in tetrahydrofuran. White crystalline solid. MS (ISP): 544.5 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.S([O-])([O-])(=O)=O.[Na+].[Na+]>[OH:16][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CC(O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
A solution of ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (444 mg, 2 mmol) in methanol (4 mL) was added sodium borohydride (76 mg, 2.0 mmol) at 0° C. slowly. After addition, the reaction mixture was stirred at 0° C. for 30 min. Two drops of saturated sodium sulfate solution were added to the reaction mixture to quench the reaction. Methanol was removed in vacuo, and water was added to the residue. The aqueous solution was extrated with ethyl acetate (x3), and the combined organic layers were dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo. The crude mixture was purified by Flash Chromatography with eluent of 40% ethyl acetate/60% hexane to give the title compound as a clear oil (252 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ 1.22-1.28 (m, 3 H) 2.63-2.75 (m, 2 H) 3.79 (s, 3 H) 4.16 (q, J=7.13 Hz, 2 H) 5.07 (dd, J=9.06, 3.78 Hz, 1 H) 6.85-6.89 (m, 2 H) 7.24-7.31 (m, 2 H). HPLC retention time: 1.973 min (method A). MS (ESI) (M+Na)+ 246.96.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: C1COCCN1
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCOCC1

Procedure:
Using 3.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) and 19 ml of morpholine, a reaction similar to that conducted in Example 142 was carried out. As a result, 3.19 g of N-(trans-4-methylcyclohexyl)-4-(2-morpholinoethoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12](O)(=O)[CH2:13][OH:14].N>>[N+:9]([C:5]1[CH:6]=[C:7]2[N:8]=[C:12]([CH2:13][OH:14])[NH:1][C:2]2=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: O=C(O)CO
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Agent: N
Product: O=[N+]([O-])c1cnc2[nH]c(CO)nc2c1
Temperature: 145 °C
Reaction time: 0.62 h
Yield: 57.9 %

Procedure:
Solid 2,3-Diamino-5-nitropyridine (prepared according to J. Med. Chem. 1997, 40, 3679-3686; 610 mg, 0.0040 mol) and solid glycolic acid (750 mg, 0.0099 mol) were combined in a sealed tube (left open) and heated to 145° C. and stirred for approx. 30-45 min (solid fuses together, liquifies then re-solidifies). After allowing to cool to rt the solid was extracted with 1N HCl. The aqueous mixture was concentrated under vacuum to leave a crude solid that was basified using conc. NH3 solution. The ammonia solution was concentrated under vacuum to leave a crude solid that was dry-loaded on to silica and purified by column chromatography (using the ISCO system) to give a solid (450 mg) that was used directly in the next step.
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[NH:12][N:11]=1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34]([NH:16][CH2:15][C:13]4[NH:12][N:11]=[C:10]([CH3:9])[CH:14]=4)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1
Reactant: Cc1cc(CN)[nH]n1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)nc2C)[nH]n1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (3-methyl-1H-pyrazol-5-yl)methanamine to react 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid instead of (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as an off-white solid (0.04 g, 12%): mp 225-226° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.30 (t, J=5.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.23-7.17 (m, 2H), 5.89 (s, 1H), 4.42 (s, 2H), 4.29 (d, J=5.7 Hz, 2H), 4.02-3.97 (m, 2H), 2.48-3.42 (m, 2H), 2.46 (s, 3H), 2.16 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.6, 161.5 (d, 1JC-F=243 Hz), 157.3, 155.0, 150.5 (br), 132.6 (d, 4JC-F=3 Hz), 129.9 (d, 3JC-F=8 Hz), 118.2, 115.4 (d, 2JC-F=21 Hz), 102.5, 46.1, 41.9, 41.5, 36.8 (br), 17.0, 10.6 (br); MS (ES+) m/z 428.9 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:7]1[CH:8]=[CH:9][C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(F)cc2C#N)cn1
Yield: 41 %

Procedure:
In analogy to example 5a, 2,5-difluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90° C. After aqueous workup and crystallization from Ethyl acetate the title compound was obtained as a white solid (yield: 41%). MS: m/e=202.3 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:12])[C@@:3]([C:9]([OH:11])=[O:10])([CH2:5][CH2:6][S:7][CH3:8])[NH2:4].Cl.C(Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:12][CH:2]([F:1])[C@@:3]([C:9]([OH:11])=[O:10])([CH2:5][CH2:6][S:7][CH2:8][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:4]
Reactant: CSCC[C@](N)(C(=O)O)C(F)F
Reactant: ClCc1ccccc1
Agent: Cl
Product: N[C@@](CCSCc1ccccc1)(C(=O)O)C(F)F

Procedure:
A mixture of α-difluoromethylmethionine (0.2 mole), concentrated hydrochloric acid (0.2 l) and benzylchloride (23 ml) is heated to reflux temperature for 24 hours. The reaction mixture is then concentrated under reduced pressure to a syrup which is dissolved in water. The aqueous solution is extracted with ether, and the aqueous phase is heated with charcoal and filtered. The precipitate is diluted with hot water to a volume of 100 ml and brought to a pH of about 4-5 by addition of aqueous ammonia. On cooling, α-difluoromethyl-S-benzylhomocysteine precipitates and is collected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]1)[C:7]2=[O:25].[BrH:26]>>[BrH:26].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:7]2=[O:25]
Reactant: CCOC(=O)N1CCC(n2c(=O)c3cccc(Cl)c3n(C)c2=O)CC1
Agent: Br
Product: Cn1c(=O)n(C2CCNCC2)c(=O)c2cccc(Cl)c21

Procedure:
In 10 ml of 48% hydrobromic acid was dissolved 451.8 mg (1.24 mmol) of 8-chloro-3-(1-ethoxycarbonyl-4-piperidinyl) -1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound a) obtained in Reference Example 7, and the solution was heated under reflux for 1 hour. After the solvent was distilled off, ethanol was added to the residue, and the precipitated crystals were collected by filtration to give 119.5 mg of crude 8-chloro-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide. The crude product was dissolved in 10 ml of DMF, and 65 mg (0.29 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 122 mg (0.87 mmol) of potassium carbonate were added thereto, followed by heating at 120° C. for 2 hours. To the reaction mixture were added water and dilute hydrochloric acid for neutralization, and the mixture was extracted with chloroform. The organic layer was washed with an aqueous solution of sodium chloride and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=50/1). Ethyl acetate and ether were added to the product, and the precipitated crystals were collected by filtration and washed with ether to give 55.2 mg (yield: 8.9%) of Compound 15 as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][O:12][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:7][C:6]=2[CH:13]=1
Reactant: OC[C@H]1COc2ccc(Br)cc2O1
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)O[C@@H](COc1ccccc1)CO2
Temperature: 0 °C
Yield: 49.1 %

Procedure:
A mixture of [(2S)-7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (2.26 g, 9.20 mmol), phenol (0.87 g, 9.2 mmol), triphenylphosphine (2.42 g, 9.20 mmol) and THF (80 mL) is cooled in a 0° C. bath under N2. Diethylazodicarboxylate (1.50 ml, 9.5 mmol) is added, and the mixture is allowed to warm to rt overnight. The mixture is adsorbed onto SiO2 and chromatographed (Biotage 40S+SIM, (1:19) EtOAc:hexane). The product fractions are pooled and concentrated to afford 1.45 g (49%) of (2S)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine as a clear oil. A mixture of this oil (14, 0.472 g, 1.47 mmol), (R)-3-aminoquinuclidine (0.557 g, 4.41 mmol), palladium acetate (0.083 g, 0.37 mmol), 1,3-bis(diphenylphosphino)propane (0.153 g, 0.370 mmol), and toluene (20 ml) are stirred under CO (g) in a 97° C. oil bath. The mixture is allowed to cool to rt and after 1.5 h is concentrated. The residue is partitioned between NaOH (aq) and EtOAc. The organic layer is separated, washed with brine, dried (MgSO4), filtered, and concentrated. The residue is chromatographed (Biotage 40 S, (1:10:190) NH4OH—MeOH—CHCl3). The product fractions are pooled and concentrated affording the product as a foam. The foam is taken up in EtOH, treated with fumaric acid (1.0 eq) and water (1 drop), and partially concentrated. Et2O is added and the resulting solid filtered and dried to provide 0.310 g (53%) of Example 11 as a monohydrate solid: 1H NMR (400 MHz, CD3OD) δ 7.49, 7.43, 7.25-7.35, 6.90-7.05, 6.70, 4.55-4.65, 4.45-4.55, 4.35-4.45, 4.20-4.35, 3.75-3.85, 3.20-3.50, 2.30-2.40, 2.15-2.30, 2.00-2.15, 1.85-2.00.
Reaction SMILES: [CH2:1]1[CH2:18][O:17][C:3]([CH3:16])([CH2:4][CH2:5][CH2:6][CH:7]([OH:15])[CH2:8][CH2:9][CH2:10][CH:11]([OH:14])[CH:12]=[CH2:13])[O:2]1>ClC(Cl)C.[O-2].[O-2].[Mn+4]>[CH2:18]1[CH2:1][O:2][C:3]([CH3:16])([CH2:4][CH2:5][CH2:6][CH:7]([OH:15])[CH2:8][CH2:9][CH2:10][C:11](=[O:14])[CH:12]=[CH2:13])[O:17]1
Reactant: C=CC(O)CCCC(O)CCCC1(C)OCCO1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(Cl)Cl
Product: C=CC(=O)CCCC(O)CCCC1(C)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sample of the crude 11,11-ethylenedioxy-3,7-dihydroxy-1-dodecene (10 g.; prepared as described above) was dissolved in dichloroethane (250 ml.), and to this solution activated manganese dioxide (60 g.) was added. The mixture was stirred for 1 hour at room temperature, filtered, and the filter cake washed 3 times, each time with 250 ml. of dichloroethane. Concentration of the combined filtrate afforded crude 11,11-ethylenedioxy-7-hydroxy-1-dodecen-3-one.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C(#N)C.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:7]2=[O:14])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 95.7 %

Procedure:
To a solution of 5-nitroisoindoline-1,3-dione (10.5 g, 53.6 mmol) in a mixture of acetonitrile (80 ml) and DMF (20 ml), potassium carbonate (9.99 g, 72.3 mmol) and tert-butyl 2-bromoacetate (10.29 ml, 69.6 mmol) were added, and the reaction was heated to reflux for 3 hours. The insoluble inorganic salts were filtered off, and the filtrate was evaporated to dryness. The residue was diluted with EtOH (60 ml) and precipitation of the desired product was observed. The precipitate was collected by filtration affording tert-butyl 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetate (15.7 g, 51.3 mmol, 96% yield, MS/ESI+ 328.9 [MNa]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]([OH:25])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]([Cl:28])=[O:25])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2C(C(=O)O)CCC2c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2C(C(=O)Cl)CCC2c2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4.05 g, 11.1 mmol) in toluene (60 ml) was added thionyl chloride (1.21 ml, 16.7 mmol) and the mixture was stirred at 80° C. for 1.5 h. Evaporation of the solvent yielded (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic chloride as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1>>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:24][N:23]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Agent: Cl
Product: Cc1ccc(Cn2cc(C#Cc3ccnc(Cl)c3)nc2C)cn1

Procedure:
The title compound, MS: m/e=323.4 (M+H30), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 5-chloromethyl-2-methyl-pyridine hydrochloride.
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([C:22]#[N:23])[S:21][C:17]=4[CH:16]=3)=[CH:11][CH:10]=2)[O:3]1.I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+]>CC(C)=O.O>[C:22]([C:20]1[S:21][C:17]2[CH:16]=[C:15]([O:14][CH2:13][C:12]3[CH:26]=[CH:27][C:9]([B:4]([OH:3])[OH:5])=[CH:10][CH:11]=3)[CH:25]=[CH:24][C:18]=2[N:19]=1)#[N:23]
Reactant: CC1(C)OB(c2ccc(COc3ccc4nc(C#N)sc4c3)cc2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3ccc(B(O)O)cc3)cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
To a solution of 6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzo[d]thiazole-2-carbonitrile (PBI 4472) (0.26 g, 0.66 mmol) in acetone (40 ml), a suspension of sodium periodate (0.43 g, 1.99 mmol), ammonium acetate (0.11 g, 1.33 mmol) in water (40 ml) was added at room temperature. The thick suspension was allowed to stir at room temperature for 18 hours. All solvent was evaporated, and the residue was dissolved in DMF. The suspension was centrifuged, and the clean solution was purified by prep-HPLC with acetonitrile/10% ammonium acetate to give the product as a white crystal (0.15 g, 72%). 1H NMR (300 MHz, DMSO, δ): 8.15 (d, J=9.0 Hz, 1H), 8.04 (s, 2H), 7.97 (d, J=3.0 Hz, 1H), 7.80 (d, J=9.0 Hz, 2H), 7.41 (m, 3H), 5.23 (s, 2H); MS (ESI) m/z 311.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH2:13][CH2:14][OH:15]>[Pd].C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: OCCC#Cc1ccc2ccccc2n1
Agent: [Pd]
Solvent: CCO
Product: OCCCCc1ccc2ccccc2n1
Yield: 96.8 %

Procedure:
4-(2-Quinolinyl)-3-butynol (2.53 g) was hydrogenated over pre-reduced 10% palladium on charcoal (50% aqueous paste, 0.6 g) in ethanol (100 ml) at room temperature and pressure. The reaction mixture was filtered through hyflo and evaporated in vacuo to afford the title compound as a colourless semi-solid (2.50 g), t.l.c. (diethyl ether), Rf 0.20.