Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]3[N:15]=[CH:16][C:17](C([O-])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.CN(C)C1C=CC=CC=1>>[Cl:23][C:12]1[N:11]2[N:15]=[CH:16][CH:17]=[C:10]2[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: O=C([O-])c1cnn2c(O)cc(-c3ccc(Cl)cc3)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1ccc(-c2cc(Cl)n3nccc3n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (9.53 g, 0.03 mol), phosphorous oxychloride (11.0 mL, 0.12 mol), and N,N-dimethylaniline (1.3 mL, 0.01 mol) was stirred for 2 h at 100° C. The mixture was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The organic phase was washed with water, dried (Na2SO4) and evaporated in vacuo. The remaining solid was crystallized from ethyl acetate/hexane to give 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (6.80 g, 67%). Pale-yellow solid, MS (ISP) 336.0 [(M+H)+]; mp 133-135° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O.Cl>CS(C)=O.[Cu]I>[C:10]([CH:12]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CCOC(=O)CC#N
Reactant: COc1cccc(I)c1
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)c1cccc(OC)c1
Temperature: 90 °C

Procedure:
A mixture of 3-iodoanisole (11.2 ml, 85 mmol), ethyl cyanoacetate (27.3 ml, 256 mmol), potassium carbonate (47.2 g, 342 mmol), copper(I) iodide (1.63 g, 8.55 mmol) and L-proline (1.97 g, 17.1 mmol) in dimethylsulfoxide (300 ml) was heated to 90° C. under argon for 11 h and then at room temperature over night. The solution was poured into 1N hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium bicarbonate, filtered and the solvent evaporated to obtain a brown oil. Purification on 12 g SiO2 using 20% ethyl acetate in cyclohexane afforded a clear oil m=16.8 g (44.8%)
Reaction SMILES: [NH2:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.[C:16]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[C:16]([O:20][C:21]([NH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NC1CN(Cc2ccccc2)CC12CC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CN(Cc2ccccc2)CC12CC2
Reaction time: 2 h
Yield: 75.3 %

Procedure:
In 30 ml of tetrahydrofuran was dissolved 800 mg of compound 6 followed by the addition of 1.2 g of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) at room temperature and the mixture was stirred at that temperature for 2 hours. The solvent was then removed under reduced pressure and to the residue was added chloroform. The mixture was extracted with a 10% aqueous citric acid. The citric acid extract was adjusted to pH≥10 with 1N aqueous sodium hydroxide and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 900 mg of 7-tert-butoxycarbonylamino-5-benzyl-5-azaspiro[2,4]heptane (compound 10). 870 mg of this compound 10 was dissolved in 15 ml of ethanol and catalytic hydrogenation was carried out at 40° C. and 4.5 kg/cm2 in the presence of 500 mg of 10% palladium-on-carbon for 2 hours. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to give title compound 11. This product was used without purification in the substitution reaction.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH2:7][CH:8]=[CH2:9])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([N:6]([CH2:7][CH:8]=[CH2:9])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])=[CH:15][CH:14]=1
Reactant: C=CCN(CCN(CC)CCCCC(C)C)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: C=CCN(CCN(CC)CCCCC(C)C)c1ccc(N)cc1

Procedure:
In a manner similar to Preparation 4 react N-ethyl-N-(5-methylhexyl)-N'-(4-nitrophenyl)-N'-(2-propenyl)1,2-ethanediamine with tin(II) chloride dihydrate in ethanol to obtain the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:17][C:16]3[C:18]4[C@@H:19]5[CH2:28][C@H:22]([C:23]=4[C:24]([O:26][CH3:27])=[CH:25][C:15]=3[CH2:14]2)[CH2:21][CH2:20]5)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][C@@H:13]1[O:17][C:16]2[C:18]3[C@@H:19]4[CH2:28][C@H:22]([C:23]=3[C:24]([O:26][CH3:27])=[CH:25][C:15]=2[CH2:14]1)[CH2:21][CH2:20]4)=[N+:30]=[N-:31]
Reactant: COc1cc2c(c3c1[C@@H]1CC[C@H]3C1)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1cc2c(c3c1[C@@H]1CC[C@H]3C1)O[C@@H](CN=[N+]=[N-])C2

Procedure:
Treatment of [(2R*,6R*,9S*)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-methanonaphtho[1,2-b]furan-2-yl]methyl 4-methylbenzenesulfonate (1.2 g, 2.30 mmol) with sodium azide (0.78 g, 11.99 mmol) generally according to the procedure described for Intermediate 24 gave (2R*,6R*,9S*)-2-(azidomethyl)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-methanonaphtho[1,2-b]furan. Treatment of the azide with palladium on carbon (10 wt. %, 0.10 g) generally according to the procedure described for Example 2 gave 0.45 g (53%) of (9-methoxy-4-oxatetracyclo[9.2.1.02,10.03,7]tetradeca-2,7,9-trien-5-yl)methylamine as a white solid, hydrochloride salt. mp>200° C. (dec); Anal. calcd. for C16H21NO2HCl: C, 63.94; H, 7.15; N, 4.97. Found: C, 64.68; H, 7.63; N, 4.5. Separation of the stereoisomers of (9-methoxy-4-oxatetracyclo[9.2.1.02,10.03,7]tetradeca-2,7,9-trien-5-yl)methylamine provided three compounds with >99% optical purity.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.[ClH:23].O1CCOCC1>>[ClH:23].[NH2:7][C@@H:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:18]([CH3:19])[CH3:20])=[O:21]
Reactant: CN(C)C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H](N)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-(1-Dimethylcarbamoyl-3-phenyl-propyl)-carbamic acid tert-butyl ester (235 mg, 0.8 mmol) was dissolved in 4 M HCl-dioxane (2 mL) at 0° C. The mixture was stirred at 25° C. for 1.5 hours, concentrated and the residue triturated with ether. Yield, 187 mg, 100%; HPLC (60/40) 2.31 minutes (99%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10](/[CH:19]=[CH:20]/[C:21]([NH2:23])=[O:22])=[CH:9][C:8]1=[O:24].FC(F)(F)C(O)=O>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10](/[CH:19]=[CH:20]/[C:21]([NH2:23])=[O:22])=[CH:9][C:8](=[O:24])[N:7]2[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=1
Reactant: COc1ccc2c(/C=C/C(N)=O)cc(=O)n(CC3OCCO3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(/C=C/C(N)=O)cc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
To 0.20 g of (2E)-3-(1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)-acrylamide, 5 mL of 80% aqueous trifluoroacetic acid solution was added, and stirred at room temperature for 4 hours, thereafter allowed to stand at the same temperature overnight. After the solvent was removed under reduced pressure, water was added and adjusted to pH 7.8 with 1.0 mol/L aqueous sodium hydroxide solution. The resulting solid was filtered to give 98 mg of (2E)-3-(7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinolin-4-yl)acrylamide as a light brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][CH2:9][C:10](=O)[N:11]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:5]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][CH2:9][C:10](=[S:31])[N:11]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)CSc2ccc([N+](=O)[O-])cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)CSc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 54.7 %

Procedure:
A mixture of ethyl 2-(6-nitro-3-oxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)propanoate (0.189 g, 0.61 mmol) and Lawesson's reagent (0.493 g, 1.22 mmol) in toluene (40 mL) was heated at reflux for 16 h. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 8% EtOAc in petroleum ether) to give ethyl 2-(6-nitro-3-thioxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)propanoate (0.109 g, 55%). TLC (eluting with 25% EtOAc in petroleum ether) Rf=0.3.
Reaction SMILES: C(OC([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:22])[C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)=O)C.[ClH:23]>>[ClH:23].[ClH:23].[OH:22][C:15]1[C:16]2[C:17]([CH3:21])=[C:18]3[CH2:19][CH2:20][NH:6][CH2:7][CH2:8][C:9]3=[N:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)N1CCc2nc3cccc(O)c3c(C)c2CC1
Agent: Cl
Product: Cc1c2c(nc3cccc(O)c13)CCNCC2
Yield: 72 %

Procedure:
10-Hydroxy-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline dihydrochloride was prepared by hydrolysis of 10-hydroxy-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester in concentrated hydrochloric acid. Yield: 72% of theory; m.p. >300° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][CH:36]([NH2:38])[CH3:37]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:30][C:29]([CH2:31][NH:38][CH:36]([CH3:37])[CH2:35][N:34]([CH3:39])[CH3:33])=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Reactant: CC(N)CN(C)C
Product: CC(CN(C)C)NCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1

Procedure:
5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde and N,N-dimethyl-1,2-propanediamine were reacted in an analogous manner to Example 10 to give the title compound; δH [2H6]-DMSO 9.83 (1H, b,), 8.70 (1H, s), 8.42 (1H, s), 8.10 (1H, d), 7.73 (1H, d), 7.64 (2H, d), 7.50-7.28 (5H, m), 7.02 (2H, d), 6.99 (1H, d), 6.52 (1H, d), 5.10 (2H, s), 3.93-3.70 (2H, m), 2.04 (9H, m), 0.92 (3H, m); m/z 508 (M+1)+.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[Na].[NH4+].[Cl-]>C(O)C>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:12]=1[CH:13]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1]2
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc2c(Br)cccc2[nH]1
Temperature: 7.5 °C
Reaction time: 0.5 h

Procedure:
A solution of 23 mL of ethyl azidoacetate and 7.6 mL of 2-bromobenzaldehyde in 40 mL ethanol was added dropwise to a solution of 4.5 g sodium in 180 mL ethanol, in a bath at −10° C., at a rate such that the reaction temperature does not rise above 8° C. After the addition is complete, the mixture is stirred at 5-10° C. for 30 min. The reaction mixture is then poured into a mixture of 28 g of NH4Cl in 1 L ice, and extracted with 1:4 CH2Cl2hexane. The organic phase is filtered through 150 mL silica gel, which is rinsed with 200 mL of the same solvent. This is evaporated to near dryness, diluted with 300 mL xylene, and stabilised with 60 mg of 2,5-di-t-butylhydroquinone. This mixture is heated with a distillation head until 50 mL of xylene has distilled. The mixture is cooled and evaporated in vacuo to a volume of 80 mL, which is diluted with 80 mL of hexane. A white solid forms upon cooling to 0° C., which is filtered off.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9](OC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[CH2:9][OH:10]
Reactant: COC(=O)c1cccc(C2OCCO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-(1,3-dioxolan-2-yl)benzoate (11.0 g., 53 mmol) in tetrahydrofuran (50 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (3.2 g) in tetrahydrofuran (100 ml). The temperature rose to ca. 45° C. The mixture was stirred for a further 1 hour cooling to room temperature, then was cooled in ice whilst water (3.2 ml) 2M sodium hydroxide (6.4 ml) and more water (6.4 ml) were added dropwise. The mixture was filtered through a pad of Celite filter acid and the filtrate was evaporated to a colourless oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccccc3)CC2)c2ccccc2-c2ccccc21
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A suspension of 0.4 g (0.93 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide, 0.153 ml (1 mmol) of 1-phenylpiperazine, 0.8 g of potassium carbonate and 1 ml water in 30 ml dimethylformamide is stirred for 10 hours at 80° C. The reaction mixture is then poured onto water, extracted with ethyl acetate and the organic phase is dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/methanol=15:1).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16](Cl)=[O:17])([O-:12])=[O:11].C1OC1C>O1CCCC1>[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:17])([O-:12])=[O:11]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CC1CO1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)O

Procedure:
(S)-Leucine (10 g) was suspended in 150 mL dry tetrahydrofuran and chilled in an ice bath while stirring under a nitrogen atmosphere. 3,5-Dinitrobenzoyl chloride (Table 2, Compound 13, 21 g) and propylene oxide (6.6 g) were added; the resulting heterogeneous mixture became clear after several minutes. The mixture was allowed to stir for 5 h, and was evaporated under reduced pressure to afford an oil which crystallized upon addition of 100 mL of cold dichloromethane. Filtration and drying of the resulting crystals afforded 3,5-dinitrobenzoyl-(S)-leucine, 14, as a white solid (20.64 g, 83% yield). 1H NMR (200 MHz, d6DMSO) δ: 0.95 (m,6H), 1.75 (M,3H), 4.25 (m,1H), 9.00 (t,1H), 9.17 (d,2H), 9.41 (d,1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.OC[CH2:27][N:28]1[C:36]2[C:31](=[C:32]([O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[Br:24][CH2:21][CH2:27][N:28]1[C:36]2[C:31](=[C:32]([O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)COc1cccc2c1ccn2CCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)COc1cccc2c1ccn2CCBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
Under argon atmosphere, triphenylphosphine (1.05 g) and tetrabromomethane (2.00 g) were added to methyl (1-(2-hydroxyethyl)indole-4-yloxy)acetate (500 mg) in methylene chloride (10 ml) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. Since the reaction had not been completed, triphenylphosphine (1.00 g) was added and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture, aqueous sodium hydrogen carbonate solution (5 ml) and water (10 ml) were added and the resultant was extracted with ethyl acetate (3×20ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (602 mg, yield: 96%).
Reaction SMILES: C1(N)CCC1.[CH3:6][CH:7]([NH:10][CH2:11][CH2:12][C:13]([NH:15][CH3:16])=[O:14])[CH2:8][CH3:9]>>[CH:7]1([NH:10][CH2:11][CH2:12][C:13]([NH:15][CH3:16])=[O:14])[CH2:6][CH2:9][CH2:8]1
Reactant: CCC(C)NCCC(=O)NC
Agent: NC1CCC1
Product: CNC(=O)CCNC1CCC1

Procedure:
Using cyclobutanamine—Aldrich and analogous conditions to Intermediate 89 the title compound was obtained as a pale yellow oil (541 mg)
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:27]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:27])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Fc1cccc(Cl)c1COc1cccnc1NC(=S)Nc1ccccc1
Product: N=C(Nc1ccccc1)Nc1ncccc1OCc1c(F)cccc1Cl
Reaction time: 72 h

Procedure:
A mixture of N-[3-(2-fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea (2 g, 0.0052 mol), yellow mercuric oxide (1.34g, 0.0062 mol) and methanolic ammonia solution (40 ml) was stirred for 72 hours. The solvent was removed in vacuo and the black residue was treated with chloroform and filtered through celite. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 1.07 g (56%), m.p. 147°-149 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:40][C:41]([F:51])([F:50])[C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[C:44]([NH2:49])[CH:43]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:49][C:44]1[CH:43]=[C:42]([C:41]([F:40])([F:50])[F:51])[CH:47]=[CH:46][C:45]=1[NH:48][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(C(F)(F)F)ccc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 132.4 %

Procedure:
6-Chloronicotinic acid (157.5 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-trifluoromethyl-o-phenylenediamine (211 mg, 1.2 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum. To the residue was added 5 ml of absolute ethanol. The solids were collected by vacuum filtration, washed with absolute ethanol and dried under vacuum to give the title compound (418 mg, 42% yield) as a brown solid. LC-MS (m/z) 316 (M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCCC2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(pyrrolidin-1-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C28H27N3O3
Reaction SMILES: C(O[CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[Cl:20])[C:6](Cl)([Cl:11])[C:7]([F:10])([F:9])[F:8])(=O)C>C(O)(=O)C.[Zn]>[Cl:11][C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[Cl:20]
Reactant: CC(=O)OC(c1cccc(Cl)c1Cl)C(Cl)(Cl)C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: FC(F)(F)C(Cl)=Cc1cccc(Cl)c1Cl
Temperature: 90 °C

Procedure:
A solution of 59.0 g of (1-acetoxy-2,2-dichloro-3,3,3-trifluoropropyl)-2,3-dichlorobenzene in 350 ml of acetic acid is heated to 40° C., and 13.0 g of zinc powder are added portionwise. To effect completion of the reaction, the reaction mixture is heated at 90° C. for 3 hours. In further processing, thereaction mixture is taken up in ice-water, and extracted with ether. The combined organic phases are washed with water, sodium hydrogen carbonate solution and sodium chloride solution; they are then dried over magnesium sulfate, and concentrated by evaporation to thus obtain (2-chloro-3,3,3-trifluoropropen-1-yl)-2,3-dichlorobenzene in the form of yellow oil (compound No. 4.10).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([N+]([O-])=O)=[C:6]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH:5]=1.[CH3:24][S-:25].[Na+]>CN1CCN(C)C1=O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([S:25][CH3:24])=[C:6]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCCc2cccc(C)c2)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: COC(=O)c1ccc(SC)c(OCCc2cccc(C)c2)c1
Yield: 66.5 %

Procedure:
The compound of step 1 (900 mg, 2.85 mmol) was dissolved in 1,3-dimethyl-2-imidazolidinone (6 ml), and sodium methanethiolate (0.23 g, 3.29 mmol) was added. The mixture was reacted at room temperature for 60 h, then partitioned between a saturated sodium chloride solution and EA, and the aqueous phase extracted with EA. The organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to give 600 mg of the title compound.