Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]Br.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>C1COCC1>[CH2:11]([O:13][P:14]([CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[F:10])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12]
Reactant: Fc1ccc(Cl)cc1CBr
Reactant: CCOP(OCC)OCC
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1cc(Cl)ccc1F)OCC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-Chloro-2-fluoro-benzylbromide (630 g, purity according to GC 72% a/a, 2.42 mol) was heated at 100° C. and triethylphosphite (403 g, 2.42 mol) was added slowly in 1 h 45. The mixture was stirred for 2 hours at 100° C., and slowly THF (350 ml) was added and distilled off, until no ethylbromide was detected by NMR. To isolate the crude (5-chloro-2-fluoro-benzyl)-phosphonic acid diethyl ester the reaction mixture was cooled to room temperature, yielding 681 grams (100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11](S(C)(=O)=O)[C:10]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)([C:17]([F:20])([F:19])[F:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)([C:17]([F:20])([F:19])[F:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)C1CN(Cc2ccccc2)CC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)C=CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
1-Benzyl-3-(3,5-dichlorophenyl)-4-(methylsulfonyl)-3-(trifluoromethyl)pyrrolidine (2.00 g, 95% purity, 4.13 mmol) was dissolved in toluene (40 mL) under a nitrogen atmosphere and sodium carbonate (1.31 g, 12.4 mmol) was added. The reaction mixture was heated to reflux for 150 minutes and cooled to room temperature. Water (20 mL) was added, the mixture stirred for 5 minutes and the phases separated. The water phase was extracted with toluene (20 mL) and solvent of the combined organic phases was evaporated under vacuum. The crude material was dissolved in warm n-heptane and after standing and cooling the forming crystals were filtered off to yield 1-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,3-dihydro-1H-pyrrole (972 mg, 95% purity, 60% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:40]=[C:39](I)[CH:38]=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24].[C:42]([NH:48][C:49]1[N:50]=[C:51]([OH:61])[C:52]2[CH:58]=[C:57]([C:59]#[CH:60])[CH:56]=[N:55][C:53]=2[N:54]=1)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl.[Cu](I)I>[F:20][C:21]1[CH:40]=[C:39]([C:60]#[C:59][C:57]2[CH:56]=[N:55][C:53]3[N:54]=[C:49]([NH:48][C:42](=[O:47])[C:43]([CH3:46])([CH3:44])[CH3:45])[N:50]=[C:51]([OH:61])[C:52]=3[CH:58]=2)[CH:38]=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24]
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(I)cc1F)C(=O)OC
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A mixture of 0.44 g (2.56 mmol) of palladium chloride and 1.34 g (5.12 mmol) of triphenylphosphine in 200 mL of acetonitrile is stirred under nitrogen at room temperature for 30 minutes. To this mixture is added an additional 150 mL of acetonitrile, 22.09 g (52.2 mmol) of dimethyl N-(2-fluoro-4-iodobenzoyl)-L-glutamate, 13.830 g (51.2 mmol) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 0.0244 g (1.28 mmol) of copper iodide, and 15 mL (107.5 mmol) of triethylamine. The reaction mixture is then heated at reflux for 3 hours and then cooled to room temperature, the solvent is then removed in vacuo and the crude solid chromatographed on silica gel with 1:19 methanol:methylene chloride to give 18.1 g (62.5%) of dimethyl N-(2-fluoro-4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]-pyrimidin-6-yl)ethynyl]-benzoyl)-L-glutamate as a white solid m.p. 204°-207° C. (dec); Rf =0.60 (1:19 methanol: chloroform), Mass (FD)=565; IR (KBr, cm-1)=813, 1151, 1201, 1270, 1375, 1444, 1481, 1490, 1527, 1548, 1598, 1623, 1649, 1670, 1741, 1753; UV (EtOH) λmax =325 (epsilon=41100), 266 (epsilon=14600), 210 (epsilon=35700).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[N:12]2)=[CH:7][CH:6]=1)[CH3:2].[F:22][CH:23]([F:25])Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([O:16][CH:23]([F:25])[F:22])=[CH:14][C:13]([C:17]([F:20])([F:18])[F:19])=[N:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: FC(F)Cl
Reactant: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2OC(F)F)cc1
Temperature: -78 °C
Reaction time: 0.05 h
Yield: 95.2 %

Procedure:
A mixture of 4-(5-hydroxy-3-trifluoromethyl-pyrazol-1-yl)-benzoic acid ethyl ester (1 g, 3.3 mmol), difluorochloromethane (3 g, 34 mmol) and potassium carbonate (0.5 g, 3.6 mmol) in DMF (9 mL) was stirred in a sealed tube at −78° C. for 3 minutes and then at 100° C. for 12 hours. The mixture was cooled to −78° C. and the precipitate was removed by filtration and washed with DMF (3×1 mL). The filtrate and washings were poured into cold water (200 mL). The resulting suspension was transferred into a centrifuge tube and the contents were centrifuged at room temperature for 10 minutes and filtered to give 4-(5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl)-benzoic acid ethyl ester (1.1 g, 94% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)N1C(=O)Cc2cc(N)ccc21
Product: NC(=O)N1C(=O)Cc2cc(NC(=O)c3ccccc3)ccc21
Yield: 90 %

Procedure:
Acylation of 5-amino-2-oxindole-1-carboxamide with benzoyl chloride substantially according to the procedure of Example 31 afforded a 90% yield of the title compound as a cream-colored solid, mp 223°-226° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([OH:21])([CH2:19][CH3:20])[CH2:17][OH:18])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=O)[CH2:23][CH3:24]>S(=O)(=O)(O)O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH2:19][CH3:20])[CH2:17][O:18][CH:22]([CH2:23][CH3:24])[O:21]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(CO)c1cc(F)cc(OCc2ccccc2)c1
Reactant: CCC=O
Agent: O=S(=O)(O)O
Product: CCC1OCC(CC)(c2cc(F)cc(OCc3ccccc3)c2)O1

Procedure:
Using the procedure described in Example 1, 2-(3-benzyloxy-5-fluorophenyl)butane-1,2-diol (1.02 g) was reacted with propionaldehyde (6 ml) in the presence of concentrated sulphuric acid (1 drop) to give 4-(3-benzyloxy-5-fluorophenyl)-2,4-diethyl-1,3-dioxolane, as an oil and as a mixture of diastereoisomers. The product so obtained was hydrogenolysed using the procedure described in the Portion of Example 6 which is concerned with the preparation of starting materials. There was thus obtained the required starting material (0.5 g, 60%), as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2.N1CCCCC1>CO>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1/[C:32](=[CH:20]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])/[C:33](=[O:39])[NH:34]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 57 %

Procedure:
3-Methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c (40 mg, 0.134 mmol) and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d obtained from step 3 of Example 6 were dissolved in 0.3 ml of methanol under stirring, and added with piperidine (0.03 ml, 0.3 mmol) to the solution. Upon the completion of the addition, the mixture was stirred at room temperature overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to obtain the title compound (Z)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 28 (40 mg, yield 57%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21](O)=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.COC1C=C([NH2:35])C=CC=1N>>[NH2:35][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[O:25][CH3:26]
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: COc1cc(N)ccc1N
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N
Yield: 50 %

Procedure:
The product was prepared according to the manner of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin4(3H)-one (the preparation of which may be found in Example K1), using 2-methoxybenzene-1,4-diamine to give the product as a yellow powder (0.19 g, 50%). LCMS m/z 384 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.00 (s, 1H), 7.95 (d, 2H), 7.60 (d, 2H), 7.00 (s, 1H), 6.80 (d, 1H), 6.75 (d, 1H), 5.05 (s, 2H), 3.80 (s, 3H), ppm.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CI.[OH-].[K+].O1CCOC[CH2:14]1>O>[CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CC1C(=O)CCC1=O
Reactant: C1COCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CC1(C)C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
Synthesized according to Agosta and Smith, J. Org. Chem. 35: 3856 (1970) A mixture of 2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), methyl iodide (6.0 mL, 96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in water (25 mL)/dioxane (75 mL) was heated at reflux. After 5 hours, a solution of KOH (2 g) and MeI (2.4 mL) in water (5 mL)/dioxane (15 mL) was added and after another 3 hours at reflux, the solution was stirred at room temperature overnight. A solution of KOH (2 g) and MeI (2.4 mL) in water (5 mL)/dioxane (15 mL) was added to the overnight reaction and heating at reflux. After 4 hours, the mixture was cooled to room temperature and extracted with ether (1×100 mL, 3×75 mL). The combined ether extracts were evaporated, the residue combined with 10% HCl (50 mL), and the resulting mixture placed in a 120° C. oil bath until it began boiling (ca. 15 minutes). The mixture was cooled to room temperature, neutralized by addition of saturated NaHCO3 solution (150 mL) and the resulting mixture extracted with CH2Cl2 (4×75 mL). The combined CH2Cl2 solution was dried (MgSO4), filtered and evaporated to leave a brown oil (10.474 g, 83 mmol, 93%) which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([P:19]([CH3:24])(=[O:23])[O:20]CC)=[CH:15][CH:14]=3)[CH:9]=2)=[CH:6][N:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[OH:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([P:19]([CH3:24])(=[O:20])[OH:23])=[CH:15][CH:14]=3)[CH:9]=2)=[CH:6][N:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1
Reactant: CCOP(C)(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3O)on2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CP(=O)(O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3O)on2)cc1
Yield: 1.4 %

Procedure:
To a solution of compound 38-g (150 mg, 0.35 mmol) in dioxane (5 mL) was added 3 N NaOH aqueous solution (2 mL). The reaction mixture was refluxed for 1 h, and diluted with water, adjusted pH to 2 with concentrated HCl. The reaction mixture was concentrated and purified by pre-HPLC to afford compound 38-1 (2 mg). 1H NMR (300 MHz, CD3OD) δ 8.84-8.56 (m, 1H), 8.77 (s, 1H), 8.44-8.46 (m, 1H), 8.10-8.14 (m, 3H), 7.89-7.95 (m, 2H), 7.70-7.77 (m, 2H), 7.34 (s, 1H), 7.00-7.16 (d, J=51.3 Hz, 1H), 1.57-1.62 (d, J=14.4 Hz, 3H). LC-MS 395 [M+H]+
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[Br:13]>>[CH3:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[Br:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1Br
Product: Cc1ccc([N+](=O)[O-])c(C)c1Br
Temperature: 80 °C

Procedure:
Fuming nitric acid (83.3 mL) (>90%) was added slowly to a solution of 2,6-dimethyl bromobenzene (27.9 g, 150 mmol) in acetric acid (167 mL) and cooled in an ice-bath (above f.p). The mix was allowed to come to rt and later heated at 80° C. for 2 h. (HPLC showed no SM). Reaction mixture was cooled and poured into ice-water with stirring. The resulting yellow solid was filtered, washed with ice-water and dried to give 28.7 g of an yellow solid which was used as such in the next step.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].[C:16](O)([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2]
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid (3.72 g, 17.44 mmol) is dissolved in 20 mL of dichloromethane, cooled to 0° C. and 0.2 g of 4-dimethylaminopyridine (DMAP) is added, followed by t-butyl alcohol and followed by 4.32 g of dicyclohexylcarbodiimide (DCC). This solution is allowed to slowly warm to room temperature over a 76.5-hour period. Thin layer chromotography (TLC) shows mainly product, and some slightly lower Rf by-products. The mixture is stirred one hour and 50 mL of dichloromethane is added and stirring continues five hours. An additional 100 mL of diethyl ether is added and the mixture filtered. The precipitate is washed with diethyl ether. The filtrate is concentrated to an oil. The crude product is chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate. The eluate is concentrated to yield (±)-cis-1,1-dimethylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][CH:10]2[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.C1[O:23][C@@H]1C.C(N(CC)CC)C>C(O)C>[CH3:18][C:16]1([CH3:19])[O:17][CH:10]2[CH2:9][N:8]([CH2:1][CH:2]([OH:23])[CH3:3])[CH2:13][CH:12]([CH3:14])[CH:11]2[O:15]1
Reactant: C[C@@H]1CO1
Reactant: CC1CN(Cc2ccccc2)CC2OC(C)(C)OC12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(O)CN1CC(C)C2OC(C)(C)OC2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
40 (175 mg, 1 mmol), (R)-(+)-propylenoxide (297 mg, 5.1 mmol), and triethylamine (285 ul, 2 mmol) are dissolved in 3 ml of ethanol and stirred at room temperature for 5 h. After evaporation the residue is dissolved in ethyl acetate, washed subsequently with 1N NaOH and brine, dried over sodium sulphate and evaporated. The crude product, 214 mg of a yellow oil, is purified by Flash-chromatography (silica gel, dichloromethane/methanol/ammonia 95:5:0.5).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:12])[CH:7]([CH3:11])[C:8]([CH3:10])=[O:9])[CH3:4].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:22])[CH3:21]>C1(C)C=CC=CC=1>[C:8]([C:7]([CH3:11])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:6]([O:5][CH2:3][CH3:4])=[O:12])(=[O:9])[CH3:10]
Reactant: CC(=O)OCCCCCBr
Reactant: CCOC(=O)C(C)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(CCCCCOC(C)=O)C(C)=O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
In a 1 L three necked flask equipped with a mechanical stirrer and reflux condenser was placed dry toluene (300 ml). The system was flushed with argon and sodium hydride (Aldrich, 60% dispersion in mineral oil) (7.2 g, 1.2 eq.) was added. Ethyl-α-methylacetoacetate (Aldrich, 21 g, 0.15 mole) was added with stirring over a 30 minutes. The resulting solution was heated under reflux for 2 hours and cooled slightly. (Note: Reaction mixture becomes a thick paste and a mechanical stirrer is essential). 5-Bromopentylacetate (Aldrich, 31.5 g, 15 mol) was added (all at once) and the suspension was heated under reflux for 12 hr, cooled, filtered and the solvent evaporated under reduced pressure. The residue was distilled under vacuum to yield 20 g (45%) of colorless liquid, b.p 90-92 (0.5 mm). 1H NMR in CDCl3 δ, 4.1-4.2 (m, 2H, O—CH2CH3): 3.5 (t, J=7 Hz, 2H, CH2OCO—); 2.2 (s, 3H, CH3CO); 2.1 (s, 3H, —COCH3); 1.5-2.0 (m, 10H, 4-(CH2)2, C—CH3, OCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.[NH:19]([C:21]([S:23][CH3:24])=[NH:22])[NH2:20]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:20]=[N:19][C:21]([S:23][CH3:24])=[N:22][C:10]=2[OH:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)C(=O)c1cc(Cl)cc(Cl)c1
Reactant: CSC(=N)NN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CSc1nnc(-c2cc(Cl)cc(Cl)c2)c(O)n1
Temperature: 78 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
(3,5-Dichlorophenyl)(oxo)acetic acid (28.0 g 129.0 mmol) was dissolved in ethanol (280 mL) and treated successively with a catalytic quantity of sulfuric acid and methyl hydrazinecarbimidothioate (20.5 g, 193.5 mmol). The resulting mixture was stirred for 1 hr at 78° C. After completion of the reaction (TLC), the mixture was concentrated in vacuo, poured into water (150 mL), and extracted with DCM (3×250 ml). The combined organic extracts were then dried over Na2SO4, concentrated in vacuo, and purified by gradient flash chromatography, affording 6-(3,5-dichlorophenyl)-3-(methylthio)-1,2,4-triazin-5-ol (19 g, 46%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.[N:13]1([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([N:16]1[CH2:17][CH2:18][N:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[CH2:14][CH2:15]1)=[O:12]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: c1cc2cc(N3CCNCC3)ccc2[nH]1
Product: O=C(C1Cc2ccccc2C1)N1CCN(c2ccc3[nH]ccc3c2)CC1

Procedure:
Prepared from 9a and 5-(piperazinyl)-1H-indole.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][N:4]2[CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH:10]=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: OCc1ncn2cc(Br)sc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1ncn2cc(Br)sc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.6 %

Procedure:
A suspension of 2-bromo-7-hydroxymethylimidazo [5,1-b]thiazole (24 mg, 0.10 mmol) in dichloromethane (3.5 ml) was added to a solution of pyridinium dichromate (47 mg, 0.13 mmol) in dichloromethane (1.5 ml), and the mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, 4A molecular sieves were added thereto, and the mixture was stirred at room temperature for 20 min. The procedure consisting of filtering the reaction mixture through Celite, adding ethyl acetate to the residue, stirring the mixture, and filtering the stirred mixture through Celite was repeated a few times. The filtrates were combined, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole-7-carbaldehyde (11 mg, 47%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:18](=[O:19])[NH:17][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a stirred solution of 1-acetylpiperazine (0.648 g) in tetrahydrofuran (10 ml) was added 4-fluorophenyl isocyanate (0.574 g) at ambient temperature. After stirring at ambient temperature for 1 hour, the solvent was removed by evaporation under reduced pressure, and the residue was triturated with diisopropyl ether to give 1-acetyl-4-(4-fluorophenylcarbamoyl)piperazine (1.25 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c2ccccc12
Temperature: 70 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
The compound obtained in Example 17-1 (269.9 mg) was dissolved in carbontetrachloride (8 ml), and N-bromosuccinimide (252.6 mg) and azobisisobutylonitrile (22.1 mg) were added to the solution. The mixture was stirred for 6 hours at 70° C. After the completion of the reaction, the solid was removed using a glass filter and the filtrate was concentrated. The residue was dissolved in chloroform and washed with 1 mol/l aqueous solution of sodium hydroxide and saturated brine. The solution was dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was dried under reduced pressure to obtain the title compound (363.3 mg) as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][CH2:11][CH2:12][Cl:13])=[C:6]([CH:8]=1)[NH2:7].Cl.[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][CH2:11][CH2:12][Cl:13])=[C:6]([NH:7][NH2:15])[CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Br)ccc1SCCCCl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NNc1cc(Br)ccc1SCCCCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-[(3-chloropropyl)sulfanyl]aniline (0.938 g, 3.3 mmol) was dissolved in TFA (4 mL). The reaction flask was cooled to 0° C. and HCl (15 mL) was added. To the resulting suspension, an aqueous solution of NaNO2 (0.25 g, 3.7 mmol, 3 mL H2O) was slowly added. The flask was warmed to rt and stirred for 2 hrs. The flask was re-cooled to 0° C. and was transferred via cannula to an aqueous solution of SnCl2.2H2O (1.49 g, 6.6 mmol, 3 mL of H2O). The solution was stirred for 3 hours. The precipitate was collected by filtration and the residue was air-dired overnight. 1-{5-bromo-2-[(3-chloropropyl)sulfanyl]phenyl}hydrazine hydrochloroide was isolated (0.800 g, 73%) was a light-brown powder. 1H NMR (CD3OD, 300 Mhz) δ7.42 (d, 1H, 8.0 Hz), 7.14-7.21 (m, 2H), 3.66 (t, 2H, 6.2 Hz), 2.97 (t, 2H, 6.9 Hz), 1.90-1.99 (m, 2H) ppm. MS (CI, NH3): 297 (base, M+H).