Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[F:36])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C=O.CC(O)=O.[BH3-]C#N.[Na+]>C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[S:27][C:21]3[C:20](=[O:35])[N:19]([C:16]4[CH:17]=[CH:18][C:13]([O:12][CH:10]5[CH2:9][N:8]([CH3:6])[CH2:11]5)=[C:14]([F:36])[CH:15]=4)[CH:24]=[CH:23][C:22]=3[CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2F)C1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(Oc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
Dissolve 3-{4-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-fluoro-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (0.491 g, 0.932 mmol) in CH2Cl2 (10 mL) and treat with TFA (3 mL), with stirring at RT for 2 h. Remove the excess reagent and solvent in vacuo. Dissolve the crude material in CH3OH (15 mL), treat with formaldehyde (0.28 mL, 3.71 mmol, 37% aqueous solution), HOAc (0.21 mL, 3.71 mmol) and NaBH3CN (0.233 g, 3.71 mmol). Stir the mixture at RT for 30 min followed by reflux for 4 h. Quench the mixture with saturated NH4Cl solution (10 mL). Dilute with water (10 mL) and saturated NaHCO3 (30 mL). Extract with EtOAc (3×50 mL). Dry the combined organic layers with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 1% Et3N, 10% CH3OH/CHCl3 to give 2-(4-chloro-phenyl)-6-[3-fluoro-4-(1-methyl-azetidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one (0.3012 g, 0.683 mmol, 74%). Dissolve the free base (0.152 g, 344.7 μmoles) in CH2Cl2 (5 mL) and CH3OH (0.5 mL). Treat the mixture with 1.0 M HCl in EtOH (344.7 μmoles; 344.7 μL). Add Et2O (50 mL), filter, and wash with Et2O (2×20 mL). Dry in a vacuum oven at RT for 2 days to give 0.14 g (83%) of the title compound. LC-MS/ES m/z (35Cl) 441.0 [M+H]+.
Reaction SMILES: [Mg].BrC(Br)C.Br[CH2:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1.[CH2:14]([Si:17]([CH3:20])([CH3:19])Cl)[CH:15]=[CH2:16]>O1CCCC1>[CH2:14]([Si:17]([CH2:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)([CH3:20])[CH3:19])[CH:15]=[CH2:16]
Reactant: C=CC[Si](C)(C)Cl
Reactant: BrCCC1OCCO1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC[Si](C)(C)CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a slurry of magnesium (2.43 g) in dry tetrahydrofuran (50 mL), few drops of dibromoethane (˜50 μL) was added under argon and stirred at room temperature for 10 min. The reaction mixture was cooled to 10° C. and 2-(2-bromoethyl)-1,3-dioxolane (10.9 g) was introduced dropwise during 10 min and allowed to stir at room temperature for 2 hours. The resulting reaction mixture was cooled to −10° C. and allyldimethylchlorosilane (6.73 g) was added dropwise during 10 min. and stirred over night at room temperature. Finally, the reaction content was quenched with aqueous NaHCO3 (15 mL) and extracted with ether (3×50 mL). The combined organic layer was dried and concentrated under mild vacuum to obtain the crude product, which was advanced to the next step without further purification (yield 9.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:34](Cl)Cl.CI>[OH-].[Na+].[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH3:34][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:16][CH:15]=1
Reactant: O=C(O)CCCC=C(c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)c1cccnc1
Reactant: ClCCl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Product: CN(CCc1ccc(C(=CCCCC(=O)O)c2cccnc2)cc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
2.0 g of 6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)-phenyl)-6-(3-pyridyl)hex-5-enoic acid are stirred overnight in 10 ml of 4N sodium hydroxide solution, 100 ml of methylene chloride, 80 mg of benzyl trimethylammonium chloride and 0.85 g of methyl iodide. Then the organic phase is separated off and the aqueous phase is acidified to pH 5. The product precipitated is separated off and taken up in methylene chloride, dried and evaporated down. Finally, the residue is chromatographed with ethylene chloride/methanol (97:3) over a silica gel column.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C3CCCCO3)=[CH:20][CH:19]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=O)[CH2:32][CH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH3:33])[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(C#CCN2CCCC2)c(F)c1
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(C#CCN2CCCC2)c(F)c1)c1ccccc1
Yield: 35868 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, (3-fluoro-4-(3-(pyrrolidin-1-yl)prop-1-ynyl)phenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (155 mg, 0.38 mmol) was reacted with propiophenone (152 mg, 1.13 mmol) to give 58 g desired product (36% yield, Z/E=1/1). m/z=426[M+1]+.
Reaction SMILES: C([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO>C1(C)C=CC=CC=1>[Cl:21][C:20]1[C:13]2[CH2:12][CH2:11][C@@:10]3([CH3:22])[C@H:15]([CH2:16][NH:8][CH2:9]3)[C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@]12CCc3c(Cl)cccc3[C@H]1CN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@]12CCc3c(Cl)cccc3[C@H]1CNC2
Temperature: 160 °C
Yield: 83.3 %

Procedure:
To a solution of cis-2-benzyl-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.882 mmol, 0.275 g) in toluene (2 ml) was added 1-chloroethyl chloroformate (6.17 mmol, 0.883 g) and the reaction mixture was heated at 160° C. for 15 min in a microwave reactor. MeOH (2 ml) was added and the mixture further irradiated at 160° C. for 5 mins. The mixture was concentrated in vacuo and then diluted with water and extracted with DCM (3×). The combined organics were dried over Na2SO4 and concentrated in vacuo to afford a residue that was purified by silica column chromatography (eluting with DCM—20% MeOH in DCM) to afford cis-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (163 mg), m/z=222.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([NH:7][CH3:8])[NH:4][CH:5]=[O:6].C(O[C:15](=[O:17])[CH3:16])(=O)C>>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([NH:4][CH:5]=[O:6])[N:7]([CH3:8])[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(NC=O)C(Cl)(Cl)Cl
Product: CC(=O)N(C)C(NC=O)C(Cl)(Cl)Cl

Procedure:
A mixture of 1,1,1-trichloro-2-methylamino-2-formamidoethane (6.85g) and acetic anhydride (17ml) was heated on a water bath for 11/2 hours. The reaction mixture was concentrated to give a oily residue which was triturated with water. The solid formed was collected, washed with water and dried (3.6g). Recrystallisation from benzene gave pure 1,1,1-trichloro-2-formamido-2-(N-methylacetamido)ethane (3.2g, m.p. 126-8)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][N:17]3[C:21]4=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]4[N:19]=[C:18]3[CH2:28][CH3:29])[CH:12]=2)[CH:7]=1)[CH3:2].CC(C)([O-])C.[K+].[CH2:37]1[CH2:41]O[CH2:39][CH2:38]1.ClC/C=C\CCl>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][N:17]4[C:21]5=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]5[N:19]=[C:18]4[CH2:28][CH3:29])[CH:12]=3)[CH:7]=2)[CH2:39][CH:38]=[CH:37][CH2:41]1)=[O:30])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1ccc2cc(Cn3c(CC)nc4c(C)cc(C)nc43)ccc2c1
Agent: CC(C)(C)[O-]
Agent: ClC/C=C\CCl
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C1(c2ccc3cc(Cn4c(CC)nc5c(C)cc(C)nc54)ccc3c2)CC=CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product of Step 3, above (52) (95 mg, 0.24 mmol), in THF/DMPU (1 ml/0.25 ml) at -78° C., was added 1.0M solution of potassium t-butoxide in THF (0.24 ml, 0.24 mmol). The solution was stirred for 15 minutes at -78° C. and cis-1,4-dichlorobut-2-ene (0.025 ml, 0.24 mmol) was added. The reaction mixture was stirred at -78° C. for 10 minutes and a second equivalent of 1.0M potassium t-butoxide solution was added. The reaction mixture was warmed to -50° C. for 15 minutes, the cooling bath was removed and the mixture was stirred at ambient temperature for 15 minutes. The reaction was then heated to 80° C. for 2 hours. The reaction was cooled to ambient temperature, quenched with concentrated acetic acid, diluted with EtOAc and extracted from brine. The combined organics were then dried over MgSO4, filtered and concentrated to dryness. The crude material was then chromatographed on silica gel using 50% EtOAc in hexanes as the eluant to yield the title compound (53) (35 mg).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](O)(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH:1]1([O:7][C:8](=[O:12])[CH:9]=[CH:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C/C=C/C(=O)O
Reactant: OC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC1CCCCC1
Temperature: 125 °C
Yield: 78.5 %

Procedure:
Cyclohexanol (220 g), crotonic acid (199 g), PTSA (8 g), and toluene (300 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 120-130° C. Water was removed azeotropically. The reaction was aged at reflux for about 4-5 hours until no more water evolved. The reaction mixture was cooled to room temperature and quenched with water (400 mL). The organic layer was separated and subsequently washed with sodium carbonate (5%, 300 mL), and further fractional distilled to provide but-2-enoic acid cyclohexyl ester (290 g) with a boiling point of 104° C. at 13 mmHg.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[O:12])[CH2:9][C:10]#[N:11])[CH3:2].C1(C)C=CC=CC=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[O:12])[CH:9]([C:27](=[O:28])[NH:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]#[N:11])[CH3:2]
Reactant: CCn1cccc1C(=O)CC#N
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
The mixture of 2.1 g of 1-ethyl-β-oxo-2-pyrrolpropionitrile, 25 ml of toluene and 1.6 g of triethylamine is treated with 1.6 g of phenylisocyanate while stirring. It is allowed to stand overnight at room temperature, evaporated and the residue dissolved in methanol. The solution is poured into 300 ml of water containing 5 ml of 5 N hydrochloric acid and the precipitate is collected. It is dissolved in 5% aqueous sodium hydroxide, the solution filtered, the filtrate re-acidified, the solids collected, washed with water, dried and recrystallized from ethanol, to yield the 1-ethyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 144°-145°.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[C:3](\[C:7]#[N:8])/[C:4](=[S:6])[NH2:5].OO>CO>[NH2:5][C:4]1[S:6][N:1]=[C:2]([CH3:9])[C:3]=1[C:7]#[N:8]
Reactant: C/C(N)=C(/C#N)C(N)=S
Agent: OO
Solvent: CO
Product: Cc1nsc(N)c1C#N
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
To a stirred solution of (2E)-3-amino-2-cyanobut-2-enethioamide (method 3) (6.83 g, 48.4 mmol) in methanol (300 mL) was added dropwise 13.6 mL (124 mmoL) of 30% hydrogen peroxide. The mixture was stirred at 60° C. for 4 h and evaporated to 60 mL in a rotary evaporator and cooled in an ice-bath. The crystallized product was filtered off and recrystallized from EtOAc to provide the pure product 5-amino-3-methylisothiazole-4-carbonitrile (5.41 g, 80%) as a white crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 8.00 (bs, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19].Br[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2>>[Cl:34][C:32]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2)=[C:24]([O:23][CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:11]3[C:6]4[O:5][CH2:4][C:3](=[O:19])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH2:14][CH2:15]2)[CH:33]=1
Reactant: CN1C(=O)COc2c(CC3CCNCC3)cccc21
Reactant: Cc1ccc2c(OCCBr)cc(Cl)cc2n1
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5C)CC3)cc(Cl)cc2n1

Procedure:
The title compound was prepared from 4-methyl-8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-7-chloro-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:21]C(OC(C)(C)C)=O)[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[C:15]([N:18]([CH3:20])[CH3:19])[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1)(=[O:3])[NH2:2].O1CCOCC1.[ClH:35]>CO>[ClH:35].[NH2:21][CH:6]([CH2:5][O:4][C:1](=[O:3])[NH2:2])[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[C:15]([N:18]([CH3:19])[CH3:20])[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1
Reactant: CN(C)c1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)c1ccc2onc(OCC(N)COC(N)=O)c2c1

Procedure:
To a solution of 0.94 g of 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-dimethylamino-1,2-benzoisoxazole in 19 ml of methanol is added 7.5 ml of a dioxane solution (2.2N) of hydrogen chloride at 5°-10° C., and they are subjected to reaction at 20°-25° C. overnight. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the residue obtained is crystallized from 2-propanol, after which the crystals are collected by filtration, to obtain 0.34 g of colorless, crystalline 3-(2-amino-3-carbamoyloxypropoxy)-5-dimethylamino-1,2-benzoisoxazole hydrochloride having a melting point of 183°-186° C.
Reaction SMILES: ClC1C=CC([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15](C)[N:16]=[C:17](C4N(CC5C=CC(OC)=CC=5)N=CC=4)[C:9]2=3)=C(C)C=1.COC1C=CC(CN2C(C(OCC)=O)=CC=N2)=CC=1.CNN.C(O)(=O)CS.ClC1C=CC(C=O)=C(C)C=1.FC(F)(F)C(O)=O.[OH-].[Na+]>>[NH:15]1[C:10]2[NH:11][CH2:12][CH2:13][S:14][CH2:8][C:9]=2[CH:17]=[N:16]1
Reactant: COc1ccc(Cn2nccc2-c2nn(C)c3c2C(c2ccc(Cl)cc2C)SCCN3)cc1
Agent: CCOC(=O)c1ccnn1Cc1ccc(OC)cc1
Agent: CNN
Agent: Cc1cc(Cl)ccc1C=O
Solvent: O=C(O)C(F)(F)F
Product: c1n[nH]c2c1CSCCN2
Temperature: 140 °C
Yield: 63 %

Procedure:
To 4-(4-chloro-2-methyl-phenyl)-3-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-1-methyl-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.32 g, 0.67 mmol, prepared using A with ethyl 1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate (WO2011079076), B with methylhydrazine, C with thioglycolic acid and 4-chloro-2-methylbenzaldehyde (Fluorochem) and D) was added trifluoroacetic acid (5 mL). The resulting mixture was heated, in a sealed microwave vessel, for about 10 min, at about 140° C., in a microwave. After cooling to rt the mixture was made basic (pH ˜8) with 2 M aqueous NaOH and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate) to give 4-(4-chloro-2-methyl-phenyl)-1-methyl-3-(1H-pyrazol-3 or 5-yl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.151 g, 0.42 mmol, 63%) as an off white solid: LC-MS (Table 1, Method e) Rt=2.83 min, m/z 360 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 2.54 (3H, s) 2.64-2.72 (1H, m) 2.77-2.86 (1H, m) 3.21-3.31 (1H, m) 3.54-3.63 (1H, m) 3.77-3.83 (1H, br s) 3.81 (3H, s) 5.69 (1H, br. S.) 6.18 (1H, br s) 7.04 (1H, dd, J=8.5, 2.0 Hz) 7.08 (1H, d, J=8.5 Hz) 7.20 (1H, br s) 7.47 (1H, d, J=2.0 Hz) 10.1 (1H, br s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:13][C:14](=[O:29])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]=[N+]=[N-])[CH:17]=2)=[CH:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:13][C:14](=[O:29])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(OCCCN=[N+]=[N-])c3)C(=O)NC2=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C2=C(c3cccc(OCCCN)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.2 %

Procedure:
To a solution of 3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy)phenyl]-1H-pyrrole-2,5-dione (0.4 g, 1 mmol) in THF (20 mL) was added Ph3P (0.25 g, 1.1 eq.), followed by the H2O (0.017 mL). The resulting mixture was stirred at room temperature for 48 h and then concentrated in vacuo. The residue was purified on a silica gel column with 8% (10% NH4OH in methanol) in CH2Cl2 to give 3-(1-methylindol-3-yl)-4-[3-(3-aminopropyloxy)-phenyl]-1H-pyrrole-2,5-dione (0.35 g) which was converted to HCl salt and recrystalized to give 3-(1-methylindol-3-yl)-4-[3-(3-aminopropyloxy)phenyl]-1H-pyrrole-2,5-dione (0.21 g) as the HCl salt.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][NH:6][C:7]([NH:9][CH2:10][C:11](OCC)=[O:12])=[O:8].[OH-].[Na+]>CO>[I:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:11](=[O:12])[CH2:10][NH:9][C:7]1=[O:8]
Reactant: CCOC(=O)CNC(=O)NCc1cccc(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CNC(=O)N1Cc1cccc(I)c1
Temperature: 20 °C
Yield: 66.3 %

Procedure:
A solution of ethyl N-{[(3-iodobenzyl)amino]carbonyl}glycinate (7.6 g) in MeOH (40 ml) was treated with aqueous 2M NaOH (21.2 ml) and stirred under nitrogen at 20° C. The mixture crushed out instantly and was quenched by adding aqueous 2M HCl (22 ml). The residue was filtered to give the title compound (4.4 g) LCMS=2.73 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-])=O.[CH2:13]([NH2:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:8]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCN
Product: CCCCCCCCCCNC(=O)c1cccc(N)c1

Procedure:
Using this procedure 3-nitrobenzoyl chloride was treated with decylamine togive 3-nitro-N-decylbenzamide, mp 86°-88°, which was hydrogenated to give 3-amino-N-decylbenzamide, mp 56°-58°, which gave nmr and mass spectra consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[CH2:20](Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10](=[O:12])[CH3:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)N1CCCC1
Reactant: ClCCl
Solvent: CO
Product: CC(=O)C(Cc1ccc(Cl)cc1)N1CCCC1

Procedure:
The title compound was prepared according to the procedure of Reference Example 10, Step C except that ethyl 3-(4-chlorophenyl)-2-(1-pyrrolidinyl)-propanoate (from Step A) was the ester used (two steps). TLC Rf=0.7 (95:5 CH2Cl2: MeOH). LC/MS m/e=252 (M+1). 500 MHz 1H NMR (CDCl3) δ 1.86 (br s, 4H), 2.03 (s, 3H), 2.66 (m, 2H), 2.78 (m, 2H), 2.98 (dd, J=2.9, 10.3 Hz, 1H), 3.08 (m, 1H), 3.43 (m, 1H), 7.12 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.Br[CH:13]([CH3:21])[C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17]>C(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C:14]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:8][C:13]=1[CH3:21]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: COc1ccc(C(N)=O)cc1
Solvent: ClCCl
Product: COC(=O)Cc1nc(-c2ccc(OC)cc2)oc1C
Temperature: 120 °C
Yield: 15.1 %

Procedure:
A mixture of 725 mg (4.80 mmol) of 4-methoxybenzamide and 1.0 g (4.80 mmol) of methyl 4-bromo-3-oxo-pentanoate was heated neat at 120° C. for 2 h. The resulting dark slurry was cooled to RT, diluted with 2 mL of DCM and purified by silica gel flash column chromatography using hexane/EtOAc (3/1) as eluent to afford 189 mg of the title compound as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ7.92 (d, 2H, J=8.9), 6.93 (d, 2H, J=8.9), 3.85 (s, 3H), 3.73 (s, 3H), 3.56 (s, 2H), 2.34 (s, 3H); low resolution MS (FAB)m/e 285 (MH+), 284 (M+).
Reaction SMILES: [NH:1]1[CH:8]=CC(N)=[N:4][C:2]1=[O:3].FS(O)(=O)=O.[F].[F:15][C:16](F)(F)[C:17]([OH:19])=O>O>[F:15][C:16]1[C:17](=[O:19])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)F
Agent: [F]
Solvent: O
Product: O=c1[nH]cc(F)c(=O)[nH]1

Procedure:
Into a solution of cytosine (11.1 g) in a mixture of trifluoracetic acid (80 ml) and water (10 ml) kept at 10° C., fluorine fluorosulfonate was blown while stirring. The cytosine was completely consumed in 90 minutes, and the total amount of fluorine fluorosulfonate used was 18 mmol. The reaction mixture was heated under reflux for 4 hours and then treated as in Example 11 to give 5-fluorouracil (10.4 g). Yield, 80%.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[S:8][C:9]=1[CH2:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:38])C=1.[Na]>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[S:8][C:9]=1[CH2:10][S:11]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc(C#N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CS(=O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 200 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-benzonitrile (prepared according to the method described in example 14) in 4 ml of dichloromethane at 0° C. was added 80 mg of meta-chloroperbenzoic acid. The resulting mixture was stirred at 0° C. for 5 hours, at room temperature for 2 hours than kept in the fridge overnight. A saturated aqueous solution of sodium hydrogenocarbonate was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of 1 to 4% acetone/dichloromethane) to give 185 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfinyl]-benzonitrile, which was transformed into 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethanesulfinyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one according to the method described in example 1.