Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)=[C:6]([CH3:16])[CH:5]=[N:4]1)[CH3:2].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:64]/[C:65](/[C:69](/[C:72]([F:75])([F:74])[F:73])=[CH:70]\[CH3:71])=[CH:66]/[CH:67]=C)[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>>[O:63]=[C:54]1[C:55]2[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:61](=[O:62])[N:53]1[CH2:52][C@@H:51]([NH:50][C:13]([C:10]1[S:11][CH:12]=[C:8]([C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[CH3:16])[CH:9]=1)=[O:15])[CH2:64][C:65]1[CH:66]=[CH:67][CH:71]=[CH:70][C:69]=1[C:72]([F:74])([F:75])[F:73]
Reactant: CCn1ncc(C)c1-c1csc(C(=O)O)c1
Reactant: C=C/C=C(C[C@H](N)CN1C(=O)c2ccccc2C1=O)\C(=C/C)C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To a mixture of 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (240 mg, 1.02 mmol) and bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (Pybrop) (568 mg, 1.22 mmol) was added DIPEA (1.77 ml, 10.16 mmol). After 10 min, 2-{(2S,4Z)-2-amino-4-[(1E)-1-(trifluoromethyl)-1-propen-1-yl]-4,6-heptadiene-1-yl}-1H-isoindole-1,3(2H)-dione (425 mg, 1.22 mmol) was added. After 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (365 mg, 63%) as a white solid: LC-MS (ES) m/z 567 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C1C(=O)N([Br:23])C(=O)C1.O>CC#N>[Br:23][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:13])([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.0 g, 9.791 mmol) was dissolved in CH3CN (40 mL), added with NBS (1.92 g, 1.1 eq.), and the mixture was stirred at room temperature for 2.5 hr. The reaction solution was added to water (40 mL), and the precipitated solid was filtered to obtain the title compound (white powder, 2.55 g, 92%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]1[NH:10][C:9](=[O:11])[C@@H:8]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[NH:7][C:6]1=[O:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O>[C:24]([NH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[NH:10][C:9](=[O:11])[C@@H:8]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[NH:7][C:6]1=[O:23])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1cc(C[C@H]2NC(=O)[C@@H](CCCN)NC2=O)c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C[C@H]2NC(=O)[C@@H](CCCNC(=O)c3ccccc3)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a solution of (3R,6R)-3-(3-aminopropyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (100 mg) in dry N,N-dimethylformamide (3 ml) was added benzoyl chloride (60 mg). The mixture was stirred at ambient temperature for 2 hours, diluted with water (15 ml) and allowed to stand overnight. The precipitated mass was collected, washed with water, and dried in vacuo to give (3R,6R)-3-(3-benzamidopropyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (45 mg).
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].O>O1CCCC1>[Cl:10][C:2]1([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH:18]([C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:21][CH:20]=2)[O:19]1
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1(Cl)OC1c1ccc([N+](=O)[O-])cc1
Yield: 71.6 %

Procedure:
5.55 g of tert.-butyl dichloroacetate in 30 ml of tetrahydrofuran and 4.99 g of 4-nitrobenzaldehyde in 30 ml of tetrahydrofuran were cooled to -20° C. and, over 20 minutes, 30 ml of a molar solution of potassium tert.-butylate in tetrahydrofuran were added dropwise at -20° C. The reaction mixture was stirred while the temperature was allowed to rise to 20° C., and it was then poured into 100 ml of water and ice, and was extracted with ether. The organic phase was washed with water saturated with sodium chloride, then with water, dried, and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with methylene chloride to obtain 6.44 g of 1,1-dimethylethyl 2-chloro-3-(4-nitrophenyl)oxirane carboxylate melting at 60° C.
Reaction SMILES: [Br:1]Br.[N:3]1[N:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[CH:6][CH:7]=1.CC([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O>[Br:1][C:6]1[CH:7]=[N:3][N:4]2[CH2:10][CH2:9][CH2:8][C:5]=12
Reactant: BrBr
Reactant: c1cc2n(n1)CCC2
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cnn2c1CCC2
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
Bromine (22.4 mL, 435 mmol) was added to a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 8 (47.2 g, 437 mmol) and NaOAc (36.2 g, 440 mmol) in AcOH (750 mL) drop wise at 0° C. The mixture was stirred at the same temperature for 10 minutes then neutralized by the addition of aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (5×200 mL) and the organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to afford 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (73.5 g).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:35][N:34]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C1COCC1>[OH:11][N:12]([CH:13]([CH2:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:35][N:34]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[N:18]=[CH:19][CH:20]=[CH:21][N:22]=1)[CH:1]=[O:3]
Reactant: O=CO
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
To formic acid (1.5 mL, 39 mmol) at 0° C. was added acetic anhydride (375 μL, 3.9 mmol) and the mixture was stirred at RT for 10 minutes. The reaction was then recooled to 0° C., and a solution of 2-[4-(hydroxyamino)-5-({4-[5-(pyridin-2-ylethynyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)pentyl]pyrimidine (403 mg, 0.79 mmol) in THF (8 mL) was then added. The reaction was brought to RT and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×5 mL). The residue was then dissolved in MeOH (10 mL) and heated to 40° C. for one hour. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtOAc) to give the title compound as a pale yellow foam (231 mg, 0.43 mmol, 54%).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[N:7][C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.[OH-].[K+]>>[CH3:11][C:10]1[C:5]([C:4]([OH:18])=[O:3])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)ccnc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccnc(-c2ccccc2)c1C(=O)O
Yield: 67.9 %

Procedure:
To a stirred, cooled (0°) solution of ethyl benzoylacetate (200 g) and concentrated ammonia in ethanol (1 L) was added crotonaldehyde (110 g) at a rate 2.5 ml/min while the temperature was kept below 10°. The mixture was warmed to room temperature overnight and concentrated in vacuo to give a yellow oily residue (260 g). The residue was treated with a mixture of con H2SO4 (100 ml), con HNO3 (130 ml) and water (580 ml) and the mixture cautiously heated on a steam bath until the evolution of NO2 had subsided, then heated for another 30 min. After cooling, the supernatant was basified with con NH4OH and extracted with diethyl ether (300 ml×10). The combined ether extracts were concentrated to leave a dark brown oily residue (38 g). Purification of the residue by silica gel column chromatography (70 - 230 mesh, 400 g, 42×5 cm, three times) using n-hexaneethyl acetate (2:1) as eluent afforded 15 g of ethyl-4-methyl-2-phenylnicotinate. Hydrolysis of ethyl-4-methyl-2-phenylnicotinate (15 g) with refluxing ethanolic KOH, followed by work-up afforded 4-methyl-2-phenylnicotinic acid (9 g) as colorless prisms, mp 210°-212°. Treatment of 4-methyl-2-phenylnicotinic acid (9 g) with polyphosphoric acid (166.7 g) at 130° for 3 hr., afforded 1-methyl-4-azafluoren-9-one, onychine, (7.5 g) as yellow prisms from n-hexane, mp 130°-131° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:31]2[CH2:32][CH2:33][N:34]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[O:14])[CH2:35][CH2:36]2)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: O=S(=O)(c1ccc(-c2ccccn2)cc1)N1CCNCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(-c3ccccn3)cc2)CC1
Yield: 54 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-[4-(2-pyridyl)phenylsulphonyl]piperazine to give 1-[4-(2-pyridyl)phenyl-sulphonyl]4-[1(4-pyridyl)piperidine-4-ylcarbonyl]piperazine in 54% yield, m.p. 224-226° C.;
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]([F:15])([F:14])[S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([NH:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:12])=[O:11]
Reactant: NCc1ccco1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(NCc1ccco1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a stirred solution of furfurylamine (0.899 g, 9.3 mmol) in pyridine (10 mL) at 0° C. was slowly added trifluoromethanesulfonyl chloride (1.300 g, 7.7 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the product (1.5 g, 85%) as a yellowish oil. 1H NMR (300 MHz, CDCl3) δ 7.43 (dd, 1H, J=1.8, 0.9 Hz), 6.38 (dd, 1H, J=3.3, 1.8 Hz), 6.36 (d, 1H, J=3.3 Hz), 5.10 (br s, 1H), 4.48 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[O:25][CH2:24]3)=[CH:17][CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)=[CH:19][CH:20]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)c2ccc(OCC3CO3)cc2)cc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CO
Product: COc1ccc(C=CC(=O)c2ccc(OCC(O)CN3CCN(c4ccccc4)CC3)cc2)cc1OC

Procedure:
A solution of 3,4-dimethoxy-4′-(2,3-epoxy-propoxy)-chalcone, 16 (1 g, 2.9 mmol) and 1-phenyl piperazine (0.45 mL, 3 mmol) in dry methanol (90 mL) was stirred at reflux for 6 h. Reaction mixture was concentrated on rotavapor and crude product purified by column chromatography to afford 18. Yield 870 mg (60%); mp 126-127° C.; MS (FAB) 503 (M++1); IR (KBr) 3426, 1652; 1H NMR (200 MHz, CDCl3) δ 8.03 (d, J=8.8 Hz, 2H), 7.76 (d, J=15.5 Hz, 1H), 7.39 (d, J=15.5 Hz, 1H), 7.31-7.20 (m, 3H), 7.16 (d, J=1.3 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.93 (d, J=7.8 Hz, 1H), 6.95-6.87 (m, 3H), 4.19-4.08 (m, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.23 (t, J=4.7 Hz, 4H), 2.90-2.85 (m, 2H), 2.69-2.61 (m, 1H); 13C NMR (50 MHz, CDCl3) δ 189.2, 162.8, 151.8, 151.6, 149.7, 144.6, 132.1, 131.1, 129.6, 128.5, 123.4, 120.3, 116.6, 114.8, 111.7, 110.7, 70.9, 65.9, 60.8, 56.5, 53.8, 49.7. Analyses calculated for C30H34N2O5: C, 71.69; H, 6.82; N, 5.57. Found: C, 71.18; H, 6.93; N, 5.32.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](O)=[O:10])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.B#B>>[Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cnc(C(=O)O)c(Cl)n1
Agent: B#B
Product: Cc1cnc(CO)c(Cl)n1

Procedure:
Reduction of 3-chloro-5-methyl-2-pyrazinecarboxylic acid (prepared by alkaline hydrolysis of the methyl ester) with diborane gives 3-chloro-2-hydroxymethyl-5-methylpyrazine which, using the above procedure, yields N-methyl-N'-[2-((3-chloro-5-methyl-2-pyrazinyl)methylthio)ethyl]thiourea.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][C:9]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[N+](=[CH2:24])=[N-]>C(OCC)(=O)C.CCOCC>[C:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][C:9]3[CH:16]=[C:15]([C:17]([O:19][CH3:24])=[O:18])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Reactant: C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)Sc1ccc(C(C)=O)cc1CC2

Procedure:
To a solution of 2-acetyl-10,11-dihydro-dibenzo[b,f]thiepin-7-carboxylic acid (U.S. Pat. No. 4,536,507 (1985)) (600 mg, 2.01 mmol) in ethyl acetate (10 mL), was added dropwise a solution of diazomethane in ether until the yellow coloration persisted. Evaporation of the solvent gave the crude title compound as a solid which was used as such.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:15]([N:14]([CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCCCCCBr
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(C)Cc1ccccc1
Yield: 163.9 %

Procedure:
Ethyl 7-bromoheptanoate (6.00 g, 25.3 mmol) was dissolved in acetonitrile (30 mL), N-methyl-benzylamine (6.53 mL, 50.6 mmol) and potassium carbonate (13.99 g, 101 mmol) were added at room temperature, and the mixture was heated to reflux for 6 hours. The mixture was left to stand for cooling, and the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried with anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give crude ethyl 7-[benzyl(methyl)amino]heptanoate (11.5 g) as a light yellow oily substance. The resulting crude product was dissolved in 60 mL of ethanol, 10% palladium-carbon (0.72 g) was added, and the mixture was stirred at 60° C. under a hydrogen atmosphere for 16 hours. The mixture was left to stand for cooling, insoluble matter was removed by filtration, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by NH silica gel chromatography (ethyl acetate:methanol=10:0→10/1, v/v) to give the title compound (4.67 g; yield, 98%) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: NCCCN1CCOCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Clc1nc(NCCCN2CCOCC2)c2cc[nH]c2n1
Yield: 123.2 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (105 mg, 0.56 mmol), 3-morpholinopropylamine (0.164 mL, 1.12 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (3 mL) was stirred at 60° C. overnight. It was then purified by HPLC to give 2-chloro-N-(3-morpholinopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (204 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH:14](C(OC)=O)[C:15]([O:17]C)=O)=[O:4].CCCCCC.C(O)(=O)C>Cl>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[CH2:14][C:15](=[O:17])[NH:11]2)([OH:2])=[O:4]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(C(=O)OC)C(=O)OC
Agent: Cl
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2C(=O)O)N1
Yield: 38.1 %

Procedure:
Dimethyl 2-methoxycarbonyl-6-nitrophenylmalonate (3.0 g) was refluxed in 50 mL of 6 N hydrochloric acid overnight. The mixture was concentrated to dryness and refluxed for 2 hours with 1.1 g of tin (11) chloride in 20 mL of ethanol. The mixture was filtered through Celite, concentrated and chromatographed on silica gel in ethyl acetate:hexane:acetic acid to give 0.65 g (37% yield) of 4-carboxy-2-oxindole as a while solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:15]([C:18]1[CH:19]=[CH:20][C:21]([F:26])=[C:22]([CH:25]=1)[C:23]#[N:24])(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:10]([F:13])([F:12])[F:11])=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([F:26])=[C:22]([CH:25]=2)[C:23]#[N:24])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1F
Yield: 46 %

Procedure:
163 mg of 1-(3,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone (VIa) (Journal of Physical Organic Chemistry (1989), 2(4), 363-6), 486 mg of 5-acetyl-2-fluoro-benzonitrile (CAS:288309-07-9) and 276 mg of potassium carbonate in 5 ml of dry toluene were refluxed for 72 hours. The solvent was then evaporated under reduced pressure and the residue was purified on silica gel (eluent hexane/ethyl acetate 6:1) affording 5-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-fluoro-benzonitrile as a yellow resin in 46% yield (solidified on standing). 1H-NMR (CDCl3, δ in ppm): 8.05-8.11 (m, 2H), 7.33-7.43 (m, 3H), 7.15 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH2:25]1[CH:30]2CNCCN2C[CH2:27][O:26]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[CH:14]([CH2:27][O:26][CH2:25][CH2:30]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1
Reactant: C1CN2CCOCC2CN1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCOCC4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]-pyrimidin-6-ylmethyl)-piperazin-2-one using octahydro-pyrazino[2,1-c][1,4]oxazine in place of piperazin-2-one. The title compound was obtained as a white solid (79 mg, 64%).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:12]2[NH:16][C@H:15]([C:17]([OH:19])=[O:18])[CH2:14][S:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:20]=[C:21]([CH3:23])[CH3:22].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:6]1([CH:12]2[NH:16][C@H:15]([C:17]([O:19][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:18])[CH2:14][S:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C=C(C)C
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2)N1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1CSC(c2ccccc2)N1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
C--tert-Butyl (2RS,4R)-2-phenyl-4-thiazolidinecarboxylate may be prepared as follows: 15 cm3 of concentrated sulphuric acid are added dropwise to a suspension of 53.7 g of (2RS,4R)-2-phenyl-4-thiazolidinecarboxylic acid in 590 cm3 of chloroform cooled to a temperature in the vicinity of 5° C. The reaction mixture is saturated with isobutene for 5 hours while stirring and while maintaining the temperature at 5° C. After returning to a temperature in the vicinity of 20° C., stirring is continued for 20 hours. The solution is brought to a pH of 8 by addition of a saturated aqueous sodium bicarbonate solution, then the aqueous phase is separated and extracted with 2 times 300 cm3 of chloroform. The combined organic phases are washed with 2 times 300 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The oily residue obtained is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (20/80 by volume)]. The fractions containing the expected product are combined, then concentrated to dryness under reduced pressure. 42.8 g of tert-butyl (2RS,4R)-2-phenyl-4thiazolidinecarboxylate are thus obtained in the form of a pale yellow oil, a (40/60 by weight) mixture of the (2R,4R) and (2S,4R) isomers, used as it is in subsequent syntheses.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[C:1]([N:8]1[CH2:12][C@@H:11]([N:22]=[N+:23]=[N-:24])[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 10 h
Yield: 79.7 %

Procedure:
Methyl (2S,4R)-1-Boc-4-[(methylsulfonyl)oxy]pyrrolidine-2-carboxylate (9 g, 27.86 mmol) obtained in Step C was dissolved in DMF (80 ml) and NaN3 (2.7 g, 41.79 mmol) was added thereto and stirred at 90° C. for 10 hours. The reaction mixture was concentrated in vacuo, extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/4) to give the title compound (6 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14]([OH:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([O:16][CH:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10](=[O:27])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(O)c2ccccc21
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(OC(C)=O)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one (previously described, 1.0 g) in acetic anhydride (20 ml) was maintained at 80° for 3 hours. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. Ether (100 ml) was added, and the resulting solution washed with water (50 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 5-acetoxy-3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as a pale yellow oil which was used without further purification.