Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH2:12][C:13]#[CH:14])=[CH:5][CH:4]=1.[OH-].[Na+].[I:17]I>CO>[I:17][C:14]#[C:13][CH2:12][O:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: II
Reactant: C#CCOCOc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(OCOCC#CI)cc1
Reaction time: 3 h
Yield: 72 %

Procedure:
1-Methoxy-4-[(2-propynyloxy)methoxy]benzene (Intermediate II-a) (9.8 g, 0.5 mol) prepared in the above example 2 and 48% w/v aqueous sodium hydroxide solution (11.0 g) were added to methanol (75 g). Iodine (14.0 g, 0.055 mol) was then added to the solution in several portions during which the inner temperature was maintained at below 10° C. The reaction mixture was stirred for further 3 hours and the solvent was then evaporated off. The residue was extracted with toluene (20 ml) and the toluene layer was washed with distilled water. Toluene was then evaporated off to obtain the desired 1-[[(3-iodo-2-propynyl) oxy]methoxy]-4-methoxybenzene (Derivative III-a)(12.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[O:6].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O.Cl>O1CCOCC1.[OH-].[Na+]>[CH3:11][S:8]([NH:7][C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=1)=[O:6])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)NC(=O)c1cccc(N)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)NC(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.1 %

Procedure:
To a solution of N-(3-aminobenzoyl)methanesulfonamide (400 mg) in dioxane (4 ml) and 1N sodium hydroxide solution (3.73 ml) was added phenyl chloroformate (351 mg) under ice-cooling, and the mixture was stirred for 2.5 hours at ambient temperature. Water was added thereto, the mixture was adjusted pH 3 with hydrochloric acid. The mixture was extracted with chloroform-methanol, and the extract was dried over magnesium sulfate and concentrated in vacuo to give phenyl 3-(methanesulfonylaminocarbonyl)phenylcarbamate (600 mg) as colorless crystals.
Reaction SMILES: O[C:2]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C>[Si:13]([C:2]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COc1ccc(C=O)c(O)c1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c([Si](C)(C)C(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Diiospropylethylamine (3.0 ml) was added to a stirred solution (under argon) of 2-hydroxy-3-bromo- -4-methoxybenzaldehyde (1.96, 8.5 mmole) in DMF (15 ml) followed by t-butyldimethlsilyl chloride (TBSCl, 1.91 g, 12.8 mmole). The reaction mixture was stirred at room temperature for 30 min and Ice (20 g) was added to the mixture. The mixture was then extracted with ether (3×25 ml). The ethereal solution was washed with water (25 ml) and saturated NaHCO3 solution (2×15 ml). The solvent evaporated to yield 2-(t-butyldimethylsilyl)-3-bromo-4-methoxy benzaldehyde as an oil (2.54 g, 7.06 mmole, 83.1%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH2:15][CH2:16][CH2:17][C:3]1=2.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C[O-].[Na+].Cl>CO>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[C:15]1[C:4]2[O:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7]=3[C:2](=[O:1])[C:3]=2[CH2:17][CH2:16]1
Reactant: COc1ccccc1C=O
Reactant: O=C(O)c1ccc2oc3c(c(=O)c2c1)CCC3
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C=C1CCc2c1oc1ccc(C(=O)O)cc1c2=O
Temperature: 45 °C
Reaction time: 7 h

Procedure:
1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, m.p. 273°-275° C. (1.6 g) was reacted with 2-methoxy-benzaldehyde (1 g) in methanol (60 ml) in the presence of sodium methylate (1.3 g) under stirring at 45° C. for 7 hours. After cooling, the reaction mixture was acidified with 37% HCl and the precipitate was filtered and washed with methanol and then with water until neutral. Crystallization from chloroform-ethanol gave 1.2 g of 3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, m.p. 291°-295° C., NMR (CH3COOD) δ ppm: 3.36 (bs) (4H, C-1 and C-2 protons), 4.09 (s) (3H, --OCH3), 7.09-7.87 (m), (4H, phenyl protons), 8.07 (d) (1H, C-5 proton), 8.41 (bs) (1H, =CH--), 8.76 (dd) (1H, C- 6 proton), 9.28 (d) (1H, C-8 proton).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:18]3[CH:35]=[CH:34][C:21]([C:22]([NH:24][CH2:25][CH:26]([OH:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:23])=[CH:20][CH:19]=3)[CH2:15][C:16]#[CH:17])[CH:8]=2)[N:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>CN(C=O)C>[C:36]([O:33][CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:25][NH:24][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([N:14]([CH2:13][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[NH:11][C:10]3=[O:12])[CH2:15][C:16]#[CH:17])=[CH:35][CH:34]=1)(=[O:38])[CH3:37]
Reactant: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCC(O)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCC(OC(C)=O)c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
p-[N-(2-Methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(2-hydroxy-2-phenylethyl)benzamide (0.105 g) was dissolved in DMF (3 ml) and acetic anhydride (34 mg) and pyridine (37 mg) were added in turn. The mixture was stirred at 20° C. for 24 hours. The mixture was evaporated and the residue was triturated with water (5 ml). The solid was filtered off, washed with water and dried in air to give N-(2-acetoxy-2-phenylethyl)-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide (0.095 g; containing 1 equivalent of water), m.p. 203°-205° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16](Cl)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:19])=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:21][NH2:22])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:19])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc(Br)cc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccc(Br)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (4-bromo-phenyl)-(2-chloro-9-methyl-9H-purin-6-yl)-amine and hydrazine monohydrate.
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>CC(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:2]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6])=[CH:12][CH:13]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 89.1 %

Procedure:
87 g (0.27 mol) of 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were dissolved in 200 ml of acetone and the solution was added dropwise to a boiling solution of 46 g (0.66 mol) of 1,2,4-triazole in 200 ml of acetone. After heating the mixture under reflux for one hour, the solvent was removed in vacuo, the residue was taken up in methylene chloride, the methylene chloride mixture was washed several times with water and the organic phase was dried over sodium sulphate. After removing the solvent in vacuo, the residue was crystallized with petroleumm ether. 75 g (89% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-2-butanone of melting point 60° to 63° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(N)cc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(N)cc2)C1

Procedure:
The title compound is prepared from a mixture of 4-(3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)benzenamine, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Sc1ccccc1Cl
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
o-Chlorothiophenol (4.5 g., 31 mmoles) and cuprous oxide (2.2 g., 15.5 mmoles) in 100 ml. of dimethylformamide were heated in an oil bath at 170°-175° C. for 1.5 hours, during which time a precipitate formed. 5-Bromofuran-3-carboxylic acid (3 g., 15.7 mmoles) was added and heating continued for 2.5 hours. The reaction mixture was cooled to room temperature, filtered, diluted with 500 ml. of water, acidified with conc. hydrochloric acid and product extracted into 250 ml. of ethyl acetate. The ethyl acetate was back-washed with 150 ml. of water and insolubles removed by filtration. Product was extracted from the ethyl acetate into 150 ml. of 1 N sodium hydroxide, the aqueous phase acidified with conc. hydrochloric acid and product reextracted into 150 ml. of fresh ethyl acetate. The ethyl acetate was back-washed with water and concentrated to an oil (3.5 g.). Recrystallization from ether/hexane gave partially purified product in two crops (575 mg., 403 mg.). These were combined and chromatographed on approximately 150 ml. of silica gel with hexane/5% acetic acid as eluant. Middle fractions afforded purified 5-(2-chlorophenylthio)furan-3-carboxylic acid (490 mg., m.p. 146°-148° C., m/e 254).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[F:7][C:8]([F:12])([F:11])[CH2:9]I.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:8]([F:12])([F:11])[F:7])[CH:6]=1
Reactant: FC(F)(F)CI
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(I)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-iodo-1H-pyrazole (960 mg, 5 mmol), 2,2,2-trifluoroethyl iodide (3.13 g, 15 mmol) and Cs2CO3(2.4 g, 7.7 mmol) in DMF (5 ml) is heated at 60° C. with stirring overnight. After cooling, the reaction mixture is partitioned between water (50 ml) and ether (20 ml). The organic layer is separated, dried (MgSO4) and concentrated to afford the title compound as an oil which solidified upon standing 1.0 g (72%). 1HNMR (CDCl3): δ (ppm) 4.70 (m, 2H), 7.56 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(O)C>O>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
A mixture of 9.0 g of 4-chloro-6-fluoro-2-phenylquinoline prepared according to the procedure described in example 9(b) and 18 ml of ethyl isonipecotate was stirred and heated in an oil bath at 160°-165° for 2 hr. It was then cooled and diluted with water. Addition of ethanol caused a solid to form which was collected to give 7.2 g of product as white prisms, mp 120°-124°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[N:7]=1.B(O)(O)[C:13]1[CH:18]=[CH:17][C:16]2[NH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:13]3[CH:14]=[C:15]4[C:16](=[CH:17][CH:18]=3)[NH:19][CH:20]=[CH:21]4)=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2ncc(I)n2n1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1ccc2ncc(-c3ccc4[nH]ccc4c3)n2n1
Temperature: 150 °C
Yield: 90 %

Procedure:
6-chloro-3-iodoimidazo[1,2-b]pyridazine (1.00 g, 4.30 mmol, 1.0 equiv), in acetonitrile (20 mL), was added 1H-indol-5-yl-5-boronic acid (1.04 g, 6.45 mmol, 1.5 equiv), bis(triphenylphosphine)palladium(II) chloride (157 mg, 0.215 mmol, 0.05 equiv), then sodium carbonate (4.83 mL, 1.0 M aqueous solution, 2.0 equiv). The reaction mixture heated in the microwave at 150° C. for 20 min. Purification by column chromatography using 2% methanol in dichloromethane elutions gave 1.04 g of the white solid, 60%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([CH3:18])[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:13]2[CH:14]=[CH:15][C:16]([OH:17])=[C:11]([CH3:18])[CH:12]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cc1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)c2ccc(Br)cc2)ccc1O
Temperature: 25 °C
Yield: 15.2 %

Procedure:
To a solution of 4-bromobenzoyl chloride (1.04 g, 4.74 mmol) and o-cresol (0.58 g, 5.33 mmol) in CH2Cl2 (20 mL) was added AlCl3 (0.76 g, 5.72 mmol) portion-wise. The mixture was allowed to warm to RT over 12 h. Water was added, and the mixture was extracted with CH2Cl2. The organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography on silica gel (EtOAc:hexanes) to yield 0.21 g (15%) of compound 32. 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 6.89 (d, J=8.3 Hz, 1H), 7.46 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.54 (d, J=1.9 Hz, 1H), 7.58 (d, 2H), 7.72 (d, 2H), 10.42 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([OH:21])[CH:11]([S:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:18][CH:19]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(Sc2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(O)C(Sc2ccc(OCc3ccccc3)cc2)C1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
(3RS,4RS)-3-Hydroxy-4-(4-hydroxy-phenylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.6 mmol) was dissolved in acetone (5 ml), and treated with K2CO3 (0.1 g, 0.7 mmol). After 1 hour refluxing, the reaction mixture was cooled to room temperature and benzylbromide (0.084 ml, 0.7 mmol) was added. Reaction mixture was refluxed for an additional 3 hours then cooled to room temperature and quenched with H2O. The aqueous phase was extracted with CH2Cl2, the combined organic phases were dried over Na2SO4, filtered and the solvent was evaporated. The residue was chromatographed over silica gel (hexane-ethyl acetate 2:1) to provide (3RS,4RS)-3-(4-benzyloxy-phenylsulfanyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.208 g, 81%) as a yellow oil, MS: m/e=402.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([C:10]([O:12]C)=O)=[CH:4][CH:3]=1.[CH3:14][NH2:15].O1CCCC1>O>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:15]([CH3:14])[C:10](=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)c1ccc(Cl)nc1CCl
Solvent: O
Solvent: C1CCOC1
Product: CN1Cc2nc(Cl)ccc2C1=O

Procedure:
Methyl 6-chloro-2-(chloromethyl)pyridine-3-carboxylate (1.5 g, 6.82 mmol) was stirred in a solution of methylamine in tetrahydrofuran (35 mL, 70.0 mmol) at room temperature overnight. Water was added and the products extracted into ethyl acetate (2×). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated in diethyl ether to give a first batch of product. The mother liquor was concentrated in vacuo and the residue purified by flash chromatography (silica, 40-100% ethyl acetate/hexanes) and combined with the first batch to afford the title compound as a white solid. LRMS (APCI) calcd for C8H8ClN2O [M+H]+ 183.0, found 183.0.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-fluorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH:29](O)([OH:33])[C:30]#[C:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:32][C:31]#[C:30][CH2:29][OH:33])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: CC#CC(O)O
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Product: O=C1c2ccccc2C(OCC#CCO)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 58 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and butynediol (435 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (271 mg, 58%). 1H NMR (300 MHz, CDCl3): 8.05-7.93 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.61-7.54 (m, 2H, Ar—H), 7.36-7.33 (m, 2H, Ar—H), 7.24-7.16 (m, 5H, Ar—H), 4.60 and 4.52 (d: AB, J=15.0 Hz, 2H, N—CH2), 4.20-4.18 (m, 2H, HO—CH2), 3.83 and 3.52 (dt: AB, J=1.8, 15.3 Hz, 2H, O—CH2), 2.42 (t, J=6.0 Hz, 1H, OH). 13C NMR (75 MHz, CDCl3): 169.24, 148.20, 145.18, 137.24, 135.88, 133.78, 132.49, 131.29, 130.78, 129.43, 128.79, 124.81, 124.43, 124.14, 95.88, 86.01, 81.28, 54.04, 52.97, 51.55, 43.60. m/z (ES): 463 [M+H]+. Anal.: calc. for C25H19ClN2O5+0.2 H2O: C, 64.36; H, 4.20; N, 6.01. Found: C, 64.11; H, 3.72; N, 5.53.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:5][C:4]([CH:16]=[CH:17][C:18]([OH:20])=O)=[CH:3]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:46][N:47]1[CH2:51][CH2:50][NH:49][C:48]1=[O:52]>CN(C)C=O>[O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][NH:5][C:4]([CH:16]=[CH:17][C:18]([NH:46][N:47]2[CH2:51][CH2:50][NH:49][C:48]2=[O:52])=[O:20])=[CH:3]1
Reactant: NN1CCNC1=O
Reactant: O=C(O)C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1)NN1CCNC1=O
Temperature: 0 °C
Reaction time: 10 h
Yield: 87.7 %

Procedure:
3-[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2pyridinyl-]-2-propenoic acid (10.85 g), 1 g of N-hydroxybenzotriazole, 0.01 g of N,N-dimethylaminopyridine and 8.24 g of dicyclohexylcarbodiimide were stirred for 30 minutes in 100 ml of dimethylformamide. After cooling to 0° C., 4 g of N-aminoimidazolidinone was added and stirring continued for 1 hour at 0° C. and 10 hours at room temperature. The resulting suspension was then heated to 60° C. and filtered. It was again suspended in 50 ml of dimethylformamide and heated to 60° C. and filtered again. The combined filtrates were evaporated at 40° C. (oil vacuo). The oily residue was stirred with 50 ml of water containing 2 g of sodium bicarbonate. After the filtration, the solid was washed with water, acetone and ether. 12.3 g of solid was obtained after drying. It was stirred together with 8 g of p-toluenesulfonic acid in 100 ml of dichloromethane for 1 hour. Filtration yielded 12.98 g of a white solid. This material was suspended in water. Recrystallization from water/dimethylformamide yielded 8.49 g of the title compound, melting point 271° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH:31]([CH3:33])[CH3:32])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Product: CC(C)NCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.065 g, 66%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.3 mmol) and isopropylamine (0.18 g, 3.0 mmol). mp 134-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH3:15])=[N:6][CH:7]=1
Reactant: Brc1ccc(I)nc1
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1-c1ccc(Br)cn1
Yield: 84 %

Procedure:
To an argon-purged and evacuated slurry of 910 mg (3.21 mmol) of 5-bromo-2-iodopyridine and 436 mg (3.21 mmol, 1.0 eq.) of 2-o-tolylboronic acid in 8 mL of toluene and 3.2 mL of 2 M aqueous sodium carbonate, was added 36 mg (0.032 mmol, 0.01 eq) of tetrakis(tri-phenylphosphine)palladium. The reaction mixture was purged and evacuated with argon twice more and then set to reflux under argon for 15 h. The reaction was cooled and partitioned between water and EtOAc. The layers were separated, and the aqueous layer extracted once more with EtOAc. The organic extracts were combined, dried over magnesium sulfate, filtered, concentrated and dried in vacuo to give the crude product as an orange oil. Purification by silica gel chromatography (7:3 CH2Cl2/hexanes) provided the title compound as a yellow oil, 666 mg, 84% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](N)[S:9][CH:10]=1)=[O:5])[CH3:2].N([O-])=O.[Na+].[ClH:16]>O.Cl[Cu]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Cl:16])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)c1csc(N)n1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The free based 2-amino-thiazole-4-carboxylic acid ethyl ester (306 mg, 1.78 mmol) and CuCl (238 mg, 2.4 mmol) were suspended in conc. HCl (8 ml) and the mixture cooled on a salt/ice bath. A pre-cooled solution of NaNO2 (166 mg, 2.4 mmol) in water (2 ml) was added over a period of 10 min. The mixture was allowed to warm to room temperature over 1 h and was stirred for a further 1 h. Water was added and the aqueous layer extracted with EtOAc (3×10 ml). The combined EtOAc layers were washed with brine, dried (Na2SO4), filtered and the solvent removed in vacuo to give the title compound.