Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.ClC(OC(Cl)C)=O>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CN1CCC(N2c3ccccc3Sc3cc(Br)ccc32)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine, 4e (0.6 g, 1.6 mmol) in 1,2-dichloroethane (10 mL) was added 1-chloroethyl chloroformate (276 μL, 2.6 mmol). The mixture was heated to reflux for 1 h, allowed to cool to rt, and evaporated. The residue was dissolved in methanol (10 mL) and heated to reflux for 1 h. Treatment with 1-chloroethyl chloroformate was repeated three more times to obtain ⅔ conversion. After work-up, the residue was purified via flash column chromatography (eluent gradient: 0 to 30% MeOH in EtOAc containing 1% triethylamine) to yield 150 mg of recovered starting material 4e and 382 mg (66%) of title compound 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e. MS m/z (MH+) 401.1/403.1.
Reaction SMILES: O[C:2]1([CH3:20])[O:6][C:5](=O)[CH:4]=[C:3]1[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[O:18][CH3:19].O.[NH2:22][NH2:23]>C(O)C>[CH3:19][O:18][C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=1[C:3]1[C:2]([CH3:20])=[N:23][NH:22][C:5](=[O:6])[CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(F)(F)F)cc1C1=CC(=O)OC1(C)O
Solvent: CCO
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1-c1cc(=O)[nH]nc1C
Temperature: 0 °C
Yield: 36.9 %

Procedure:
5-Hydroxy-4-[2-methoxy-5-(trifluoromethyl)phenyl]-5-methylfuran-2(5H)-one (Preparation 40, 3 g, 10 mmol) was dissolved in ethanol and cooled to 0° C. Hydrazine monohydrate (1.0 mL, 20 mmol) was added drop-wise to this solution, then the reaction mixture was heated to 90° C. for 16 hours. The reaction mixture was then concentrated in vacuo, azeotoped with toluene and the crude material purified by silica gel column chromatography (ISCO™ Companion, 50% ethyl acetate in heptane elution) to afford the title compound as an off-white solid (1.05 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].[C:8]([N:13]=[C:14]=[S:15])(=[O:12])[O:9][CH2:10][CH3:11]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:14]([NH:13][C:8](=[O:12])[O:9][CH2:10][CH3:11])=[S:15]
Reactant: Nc1cnccn1
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1cnccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with pyrazin-2-amine (7.6 g, 80.0 mmol, 1.0 eq.), O-ethyl carbonisothiocyanatidate (12.5 g, 95.4 mmol, 1.2 eq.), and dioxane (150 mL). The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, it was concentrated to a volume of around 20 mL under reduced pressure and the resulting suspension was filtered. The solid was collected and washed with ethyl acetate (3×20 mL) to afford 270a (14.0 g, 77%) as a white solid. MS-ESI: [M+H]+ 227.3
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]2=[O:34])([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH:35]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)=[CH2:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][C:18]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([S:43]([C:40]3[CH:41]=[CH:42][C:37]([CH:35]=[CH2:36])=[CH:38][CH:39]=3)(=[O:45])=[O:44])[CH2:30][C:29]2=[O:34])([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20]1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(C(=O)OC(C)(C)C)CC3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
Triethylamine (735 mg) was added to a solution of 1-{[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidinyl]methyl}-2-piperazinone (1.4 g) in dichloromethane (80 ml), and 4-vinylbenzenesulfonyl chloride (885 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. An aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane, dried, concentrated, and purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain the colorless amorphous title compound (1.50 g).
Reaction SMILES: [CH:1]1([CH2:8][S:9]([O-:12])(=O)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].S(Cl)([Cl:16])=O>>[CH:1]1([CH2:8][S:9]([Cl:16])(=[O:12])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)([O-])CC1CCCCCC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Product: O=S(=O)(Cl)CC1CCCCCC1

Procedure:
The subtitle compound was prepared by the method of Preparation 58 from sodium cycloheptylmethanesulfonate [Preparation 67] and thionyl chloride, to afford cycloheptylmethanesulfonyl chloride as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[C:30]([O:32]C)=[O:31].[OH-].[Na+].CO>C1COCC1>[CH3:1][C:2]1([CH3:34])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:3]1[C:30]([OH:32])=[O:31]
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)CCSC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)O
Yield: 84.1 %

Procedure:
A solution of 0.418 g (0.817 mmol) of methyl 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate, 4.0 mL (4.08 mmol) of 1N NaOH, 4.0 mL of methanol and 4.0 mL of THF was heated to reflux for 5 h. The reaction was concentrated and the residue was diluted with water, acidified to pH5 and extracted with ethylacetate. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 0.342 g (84%) of 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid as a colorless oil. Electrospray Mass Spec: 496.5 (M−H)−
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[CH:10][CH:9]=1)=[O:6])([CH3:4])[NH2:3].C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:31](=[O:33])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[CH:10][CH:9]=2)[C:5]1=[O:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(Oc2ccc(NC(=O)C(C)(C)N)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cc2)c1
Reaction time: 0.5 h
Yield: 144 %

Procedure:
To a solution of 2-methyl-N1-(4-{[3-(methyloxy)phenyl]oxy}phenyl)alaninamide (Intermediate 72, 1.33 g) and triethylamine (3.70 mL, 26.6 mmol) in dry dichloromethane (80 mL) at 0° C. was added dropwise a solution of triphosgene (600 mg, 2.022 mmol) in dry dichloromethane (20 mL) and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with a saturated solution of ammonium chloride (100 mL) and two phases were separated. Aqueous layer was extracted with dichloromethane (100 mL) and the two organic phases were collected, dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Biotage system, 100 g SNAP cartridge) using as eluent a gradient and cyclohexane/ethyl acetate from 80/20 to 40/60 to afford the title compound as a white solid (950 mg).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][CH:24]=2)=[O:22])[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH:1]([O:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]2[N:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][CH:24]=2)=[O:22])[CH2:19][CH2:20]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccc(C(=O)N2CCC(OC(c3ccccc3)c3ccccc3)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(C(=O)N2CCC(OC(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Into a 50-mL recovery flask (eggplant flask), 250 mg (0.58 mmol) of methyl 6-(4-benzhydryloxypiperidine-1-carbonyl)pyridine-2-carboxylate synthesized in Production Example 42 was fed, and the compound was dissolved in 10 mL of ethanol. To the flask, 0.9 mL of 1-N sodium hydroxide was added, and the reaction was conducted at a room temperature. After the completion of the reaction was confirmed, the contents in the system were concentrated, and the residue was diluted with water. The diluted residue was neutralized with 1-N hydrochloric acid, and the resulting white crystal was filtered by suction, and the separated product was dried under a reduced pressure to give the title compound (200 mg (83%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:13]I>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+].[Ag+]>[CH3:13][O:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: CCOC(=O)c1ccnc(O)c1
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(OC)c1
Yield: 86 %

Procedure:
A mixture of ethyl 2-hydroxy-pyridine-4-carboxylate (1.0 g, 6 mmol), (Chem. Abs. 1957, 8740c), methyl iodide (1 ml) and silver(I)carbonate (1.64 g) in toluene (20 ml) was heated at reflux for 2 hours. The mixture was allowed to cool and the insolubles removed by filtration through diatomaceous earth and the pad was washed through with ethyl acetate. The filtrate was washed with water, dried (MgSO4) and the solvent removed by evaporation to give ethyl 2-methoxy-pyridine-4-carboxylate (0.93 g, 86%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12]Br)[CH:8]=[CH:7]2.[CH3:14][NH2:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][NH:15][CH3:14])[CH:8]=[CH:7]2
Reactant: BrCc1ccc2cccc(Br)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1ccc2cccc(Br)c2n1
Reaction time: 0.5 h

Procedure:
To a solution of 3 (1 g, 3.32 mmol) in THF (5 mL) was added methylamine (10.5 mL of 40% water solution). The solution was stirred for 30 min and then extracted with EtOAc (30 mL). The organic phase was washed with DI water (2×20 mL), dried and concentrated to give a red oil. Purification by chromatography (MeOH/DCM 1:99) yielded yellow solid.(0.8 g, 96%) 1H NMR (400 MHz CDCl3) δ8.09 (1H, d, J=8.4 Hz), 8.02 (1H, d, J=7.2 Hz), 7.77 (1H, d, J=8 Hz), 7.49 (1H, d, J=8.4 Hz), 7.36 (1H, t, J=8.0 Hz), 4.12 (2H, s), 2.58 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[CH:12][NH:13][C:6]=12>CC(O)=O.[Fe]>[NH:13]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=2[F:1])[CH:11]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of 267 (35 mg, 0.13 mmol) in AcOH (1 mL) at 90° C., was added iron powder (36 mg, 0.65 mmol). The reaction mixture was stirred vigorously for 10 min, cooled, filtered through a Celite pad and concentrated. The residue was partitioned between DCM and NaHCO3 saturated solution. Phases were separated; the aqueous phase was neutralized with AcOH and extracted with DCM. Primary organic phase and the extract were combined and concentrated to give the title compound 268 (31 mg, 99%) as an off-white solid. MS (m/z): 244.1(M+H) (found).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl.O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
A suspension of glycine ethylester, monohydrochloride (13.96 g, 100 mmol) and benzophenone imine (18.1 g, 100 mmol) in distilled dichloromethane (600 mL) was stirred at room temperature (RT) for 24 hours (h.). The mixture was diluted with water (250 mL) and the dichloromethane extract was separated, dried (MgSO4), filtered and concentrated under reduced pressure and in vacuo to obtain ethyl-N-(diphenylmethylene)-glycinate as a white solid (25.3 g, 95%). Ref.: M. J. O'Donnell, R. L. Polt J. Org, Chem. 47, 2663, 1982.
Reaction SMILES: [O:1]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([OH:18])=[O:17].S(=O)(=O)(O)O.[CH3:24]O>CCOCC>[O:1]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17]
Reactant: O=C(O)CCC1CCCCCCCCCCC1=O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)CCC1CCCCCCCCCCC1=O
Yield: 83 %

Procedure:
A solution of 3-(2-oxocyclododecyl)-propionic acid (7.0 g, 27.5 mmol) in methanol (80 mL) was treated with concentrated sulfuric acid (0.3 mL, 5.4 mmol) and the mixture heated under reflux for 1 hour. After concentration of the reaction mixture in vacuo the residue was diluted with ether (1.1L) and washed sequentially with saturated sodium bicarbonate (100 mL) and water (2×100 mL). The organic phase was dried over magnesium sulfate and evaporated in vacuo to a crude oil (7.1 g, 96%). Purification by flash column chromatography on silica gel (100:1 ratio) by elution with hexane/ethyl acetate (95/5) afforded 6.1 g (83% yield) of the title compound as a waxy solid on cooling, m.p. 33°-35° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H](C(O)=O)CC(C)C)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH3:27]>C1COCC1.O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:14](=[O:15])[C@H:12]([CH2:11][CH:6]([CH3:7])[CH3:5])[NH2:27])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](N)C(=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine, acid chloride (3.5 g, 10 mmol) in 10 mL of THF was charged with NH3 (29.6% water solution, 1.26 mL, 20 mmol) at room temperature. The reaction mixture was stirred for 30 min., then diluted with 100 mL of water and extracted with ethyl acetate (5×20 mL). The organic layers were combined, extracted with 10% potassium carbonate solution, washed with water, brine, dried and evaporated. Recrystallization of the product from ethanol afforded 1.26 g (36%) of N-(9-fluorenylmethoxycarbonyl)-L-leucine, amide as colorless solid, mp 79°-80° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]C#N)=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([O:19]CC)=O.[O-]CC.[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccn1
Reactant: N#CCc1ccc(F)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)c1ccccn1
Yield: 41.9 %

Procedure:
Combine a solution of 4-fluorophenylacetonitrile (1.00 g, 7.4 mmol) and ethyl picolinate (1.12 g, 7.4 mmol) in absolute ethyl alcohol (15 mL) under N2 with 21 wt % sodium ethoxide solution in denatured ethyl alcohol (4.2 mL, 11.1 mmol) and heat to reflux for 2 hours, then pour onto ice. Adjust the pH to 4 with concentrated hydrochloric acid and collect the precipitate by vacuum filtration. Dissolve the residue in 48% aqueous hydrobromic acid (25 mL) and heat to reflux for 2 hours. Pour the solution onto ice and adjust the pH to 7 with 5N aqueous sodium hydroxide solution. Extract the aqueous solution three times with CH2Cl2. Combine the organic extracts, dry (Na2SO4), filter, and concentrate in vacuo to afford the title compound 668 mg (42%) as a brown amorphous solid. MS FAB+ m/z=216.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11]S(=O)(=O)[NH:9]2)=[CH:4][CH:3]=1.C1(O)C=CC=CC=1>Br.C(O)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]([NH2:11])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([NH2:9])[CH3:22])=[CH:14][CH:15]=1
Reactant: CC1(c2ccc(Cl)cc2)NS(=O)(=O)NC1c1ccc(Cl)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: CC(N)(c1ccc(Cl)cc1)C(N)c1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 50.8 %

Procedure:
A suspension of rac-(3R*,4S*)-3,4-bis(4-chlorophenyl)-3-methyl-1,2,5-thiadiazolidine-1,1-dioxide (3.71 g, 10.4 mmol) and phenol (4.86 g, 52 mmol) in 48% hydrobromic acid (13.56 mL) and acetic acid (46.44 mL) was stirred at 130° C. for 40 min (reaction progress monitored by TLC), then allowed to cool to room temperature. The crude reaction mixture was partitioned between ethyl acetate and water, and the aqueous phase washed twice with ethyl acetate. The aqueous phase was then made basic by the slow addition of solid sodium hydroxide (60 g; CARE! Exothermic) and extracted with diethyl ether (3×500 mL). The combined ethereal extracts were washed with 2M sodium hydroxide (100 mL), then dried over anhydrous sodium sulfate (with a few pellets of solid sodium hydroxide) and evaporated to give the title compound (1.56 g). This material was carried forward to the next step without any further purification.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH2:15]1[O:21][CH:18]([CH2:19]Br)[O:17][CH2:16]1>>[CH3:2][N:3]([CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[CH2:19][CH:18]1[O:21][CH2:15][CH2:16][O:17]1
Reactant: BrCC1OCCO1
Reactant: CNCc1cccc2ccccc12
Agent: Cl
Product: CN(Cc1cccc2ccccc12)CC1OCCO1

Procedure:
In a similar manner, the reaction of N-methyl-1-naphthalenemethylamine hydrochloride with bromoacetaldehyde ethylene acetal gives methylnaphthylmethyl-[1,3]-dioxolan-2-ylmethylamine.
Reaction SMILES: [I:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[O:8][C:9](=O)[C:4]=2[CH:3]=1.O.[NH3:18]>>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][CH:16]=1)[N:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:18][C:9]2=[O:8]
Reactant: N
Reactant: O=c1oc(C(F)(F)F)nc2ccc(I)cc12
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)nc2ccc(I)cc12
Temperature: 0 °C

Procedure:
6-iodo-2-trifluoromethyl-benzo[d][1,3] oxazin-4-one (0.6 g, 1.76 mmole) was stirred with 25 mL of concentrated ammonia water at 40° C. for 5 h, cooled to 0° C., the precipitate was filtered and dried under vacuo. The product was recrystallized from ethyl acetate and haxanes to give 0.58 g, mp >255° C. (sub), MS (CI): m/z 341 (MH)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(N(CCCC)CCCC)CCC.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH2:35])=[CH:32][CH:31]=1.Cl>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:35][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:32][CH:31]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: COC(=O)c1ccc(C=Cc2ccc(F)cc2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A mixture of dimethyl 4-bromoisophthalate (54.75 g., 200.5 mmol), water (330 ml), tributylamine (55.63 g., 300.7 mmol), 4-fluorostyrene (55.63 g., 300.7 mmol) and bis(triphenylphoshine)palladium(II)chloride (2.81 g., 4.01 mmol) was heated at reflux with stirring under an inert atmosphere for 6 hours. The reaction was cooled to ambient temperature and acidified to pH 2 with 2M HCl (700 ml). The aqueous layer was removed and the residual solid washed with water (2 L), dissolved in dichloromethane (1 L) and passed through a pad of silica, eluting with more dichloromethane (2 L). Evaporation of the dichloromethane gave a solid, which was further washed with iso-hexane (1 L), and dried to give methyl 4-[2-(4-fluorophenyl)ethenyl]-3-methoxycarbonylbenzoate (56.75 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:17][CH3:18])[CH:6]=1.Cl>CS(C)=O>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(SC)c([N+](=O)[O-])cc1C(=O)O
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In a stream of argon, 0.45 g of sodium methanethiolate was added to 5 ml of dimethyl sulfoxide at room temperature, and 0.50 g of 4-chloro-5-nitro-2-methoxybenzoic acid was added in small portions, followed by 2 hours of stirring. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 0.45 g of 2-methoxy-4-methylthio-5-nitrobenzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:16][CH2:15][N:14]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](=[O:46])([O-])[O-].[K+].[K+]>C(#N)C>[CH3:9][O:8][CH2:1][CH:2]([N:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:16][CH2:15][N:14]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:22][CH2:21]1)[CH2:3][O:46][CH3:43]
Reactant: O=C(OCc1ccccc1)N1CCNCCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC(COC)N1CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Yield: 400 %

Procedure:
39 g (154.6 mmol) of the title compound of Example 5a and 44.43 g (77.3 mmol) of 1,4,7-tris-(benzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane (produced according to Chem. Soc., Perkin Trans. 1, 12:3329, 1991) and 85.14 g (616 mmol) of potassium carbonate in 800 ml acetonitrile are refluxed for 24 hours. Solid is filtered out, and the filtrate is evaporated to dryness in a vacuum. The residue is taken up in 700 ml of methylene chloride and extracted twice with 300 ml of water. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent =methylene chloride/methanol 20:1).