Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.O[NH:37][C:38]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([CH2:49][OH:50])=[CH:43]2)=[NH:39]>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:39]=[C:38]([C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44]([CH2:49][OH:50])=[CH:43]4)[N:37]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1ccc2[nH]c(CO)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(CO)cc4c3)no2)cc1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (150 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 10 min. N-Hydroxy-2-(hydroxymethyl)-1H-indole-5-carboximidamide (D25) (144 mg) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was heated to 80° C. and stirred at that temperature for 7 hours. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was recrystallized from EtOAc/ether to afford [5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]methanol (E11) (95 mg) as a light brown solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 4.65 (2H, d), 4.89 (1H, m), 5.36 (1H, t), 6.46 (1H, s), 7.47 (2H, m), 7.78 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d), 8.27 (1H, s), 11.43 (1H, s). MS (ES): C20H18ClN3O3 requires 383; found 384.0 (M+H+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2C=CN[N:18]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1.[N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2NC=1C(=CN(C)C)C(C1C=CC([Cl:53])=CC=1Cl)=O>>[ClH:3].[ClH:53].[N:18]1[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[NH:35][C:17]=1[C:16]1[C:11]([C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])=[N:12][C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)=[N:14][CH:15]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1nc2ccccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3cc[nH]n3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3nc4ccccc4[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
Made using the same procedure as for [4-(2,4-dichlorophenyl)-5-pyrazolylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine dihydrochloride except that 2-benzimidazolyl-1-(2,4-dichlorophenyl)-3-(dimethylamino)prop-2-en-1-one (XIV, 468 mg, 1.3 mmol) was used and the crude product was purified by recrystallization (CH2Cl2/Et2O/hexanes).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>CCO>[NH:20]([C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:21]
Reactant: CN(c1ccccn1)S(=O)(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN(c1ccccn1)S(=O)(=O)c1ccc(NN)nc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A solution of 1.4 g (4.9 mmol) of 6-chloro-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide and 0.96 mL (19.7 mmol) of hydrazine monohydrate in 8 mL of EtOH is heated for 12 hours at 80° C. The precipitate obtained, after cooling to room temperature, is filtered off, washed with 10 mL of EtOH and then dried under vacuum. 0.85 g of 6-hydrazino-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide is obtained in the form of pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH:11]=[CH:12][CH:13]=2)[C:8]([N+:23]([O-:25])=[O:24])=[CH:7]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[C:8]([N+:23]([O-:25])=[O:24])=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cc([N+](=O)[O-])c2c(CC(=O)OC(C)(C)C)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1cc([N+](=O)[O-])c2c(CC(=O)O)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-indol-4-yl]acetate from Step E (300 mg, 0.828 mmol) in CH2Cl2 (1 mL) was added TFA (0.63 mL, 8.28 mmol). The mixture was stirred at ambient temperature for 1 h then concentrated in vacuo to give the title compound. MS: m/z=307 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28]([OH:30])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[C@@H:41]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@H:40]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:56]([O:55][C:54]([NH:53][C@H:40]1[C@H:41]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@@H:42]([CH3:44])[CH2:43][N:38]([C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[NH:31][C:28]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:39]1)=[O:60])([CH3:57])([CH3:58])[CH3:59]
Reactant: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (0.005 g, 0.01 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.0064 g, 0.015 mmol), and HATU (0.012 g, 0.031 mmol) in DMF (0.2 mL) and DIPEA (0.0064 mL, 0.037 mmol) was stirred at room temperature for 2 h. The mixture was quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, then purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.05% TFA, at a flow rate of 30 mL/min.) to afford the sub-title compound (0.0032 g, 30%). LCMS calc. for C44H60N7O7Si [M+H]+: m/z=826.4. found: 826.4.
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)(Cl)Cl.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2>N1C=CC=CC=1>[Br:1][C:13]1[CH:14]=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][C:9]([Cl:8])=[CH:18][CH:17]=2
Reactant: BrBr
Reactant: Clc1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2ncc(Br)cc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The synthesis was done by the same procedure as that of J. J. Eisch (J. Org. Chem. Vol. 27, p.1318, 1962). Bromine (79 μl) and carbon tetrachloride (2 ml) were added to 6-chloroquinoline (250 mg) and stirred at 90° C. for two hours. Pyridine (123 μl) was added to the reaction solution and stirred at the same temperature for 16 hours. The reaction solution was concentrated and purified with a silica gel chromatography (hexane-ethyl acetate) to obtain the title compound (250 mg).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:23]=2)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][CH:3]=1.[Cl:34][C:35]1[C:36]([OH:46])=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1.CCN(CC)CC>C1COCC1>[Cl:34][C:35]1[C:36]([OH:46])=[C:37]([S:42]([N:7]([CH2:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:23]=2)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=2)(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(CNCc2ccc(F)cc2)cc(Oc2ccc(F)cc2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a solution of tert-butyl 3-((4-fluorobenzylamino)methyl)-5-(4-fluorophenoxy)benzylcarbamate (0.72 g, 1.58 mmol) in THF (15 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (0.41 g, 1.58 mmol) and Et3N (0.66 mL, 4.75 mmol). The reaction mixture was stirred at rt for 1.5 h. The mixture was concentrated. The sample was purified by flash chromatography. Elution with 0 to 35% of ethyl acetate in dichloromethane gave the product as a white solid (0.65 g, 61%). 1H NMR (CDCl3): δ 9.01 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.45 (s, 1H), 7.15-7.06 (m, 4H), 7.01-6.92 (m, 4H), 6.76 (s, 2H), 6.54 (s, 1H), 4.41 (s, 2H), 4.32 (s, 2H), 4.21 (d, J=5.6 Hz, 2H), 1.49 (s, 9H); MS (ESI): (M−H)−=677.1.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14]1([O:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[O:20]([C:21]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)CCO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CCOC(=O)Oc1ccccc1

Procedure:
To a 500 ml three-necked round-bottomed flask equipped with an internal thermometer, reflux condenser, mechanical stirrer, addition funnel, and argon inlet are added N,N-dimethylethanolamine (25.00 g, 0.281 mol), toluene (200 ml), and triethylamine (31.21 g, 0.309 mol). The mixture is treated with a solution of phenylchloroformate (43.91 g, 0.281 mol) dissolved in 50 ml of toluene over 15 min. After addition is complete, the mixture is heated to reflux for 3 h. The cooled mixture is washed with saturated sodium bicarbonate solution (2×100 ml) and water (100 ml). The organic phase is dried over MgSO4, filtered, and concentrated first by rotary evaporation at 50° C. (water aspirator vacuum) and then at 60° C. (0.05 mmHg) in a Kugelrohr oven to give 8 as a light yellow oil, 49.93 g (85%) that crystallizes on standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[C:6]([C@H:9]2[CH2:11][O:10]2)[C:7]=1[F:8].[CH3:19][C:20]([NH2:31])([CH3:30])[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH3:30][C:20]([NH:31][CH2:11][C@H:9]([C:6]1[CH:5]=[C:4]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=[C:2]([F:1])[C:7]=1[F:8])[OH:10])([CH3:19])[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCc1cc(F)c(F)c([C@H]2CO2)c1
Reactant: CC(C)(N)CCCc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CNC(C)(C)CCCc2ccccc2)c1
Yield: 77.6 %

Procedure:
A solution of ethyl 3-{3,4-difluoro-5-[(2S)-2-oxiranyl]phenyl}propanoate (11.07 g, 43.2 mmol) and (1,1-dimethyl-4-phenylbutyl)amine (7.68 g, 43.4 mmol) in ethanol (50 mL) was heated at 70° C. for 36 h. The reaction was concentrated and purified by column chromatography (0-90% ethyl acetate:hexane) afforded the desired product (14.54 g, 78%). MS (m/z): 434.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][N:24]1[N:28]=[N:27][C:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[CH:32]=O)=[N:25]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:32][C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([C:26]5[N:27]=[N:28][N:24]([CH3:23])[N:25]=5)[CH:30]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1nnc(-c2cccc(C=O)c2)n1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CC(=O)O
Solvent: CO
Product: Cn1nnc(-c2cccc(C=Nc3n[nH]c4ncnc(Nc5cccc(Cl)c5)c34)c2)n1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 565 mg (3.0 mmol) of 3-(2-methyl-tetrazol-5-yl)-benzaldehyde to form 4-(3-chloro-phenylamino)-3-[{3-(2-methyl-tetrazol-5-yl)-phenyl}-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H, analogous working-up and digestion in methanol yield 4-(3-chloro-phenylamino)-3-[3-(2-methyl-tetrazol-5-yl)-benzylamino]-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf=0.51 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=8.7; FAB-MS: (M+H)+=433.
Reaction SMILES: [F:1][CH:2]([F:9])[CH2:3][N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.[CH2:10]=[O:11]>>[F:1][CH:2]([F:9])[CH2:3][N:4]1[C:8]([CH2:10][OH:11])=[N:7][CH:6]=[N:5]1
Reactant: FC(F)Cn1cncn1
Reactant: C=O
Product: OCc1ncnn1CC(F)F
Temperature: 25 °C

Procedure:
1-(2,2-Difluoroethyl)-1H-[1,2,4]triazole (4.0 g, 0.030 mol) was heated at reflux in 37% aqueous formaldehyde for 2 days. The solution was allowed to cool to room temperature and was washed with dichloromethane (3×50 ml). The solution was then saturated with sodium chloride, and washed again with dichloromethane (3×50 ml). The combined organic washings were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 0 to 7.5% methanol in dichloromethane, yielding [2-(2,2-difluoroethyl)-2H-[1,2,4]triazol-3-yl]methanol as a solid (2.4 g). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ 4.65 (2H, td, J=13.2, 4.3 Hz), 4.83 (2H, s), 6.17 (1H, tt, J=55.2,4.3 Hz), 7.86 (1H, s).
Reaction SMILES: [CH3:1][Li].CON(C)[C:6]([CH:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]1)=[O:7]>C1COCC1>[F:14][C:11]1([F:15])[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[CH3:1])[CH2:9][CH2:10]1
Reactant: CON(C)C(=O)C1CCC(F)(F)CC1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C1CCC(F)(F)CC1
Temperature: 25 °C

Procedure:
2 ml methyl lithium (1 M in diethylether) were added into a solution of 0.593 g 4,4-difluoro-cyclohexanecarboxylic acid methoxy-methyl-amide in anhydrous 5 ml THF at 0° C. The reaction was allowed to warm to rt overnight. The reaction was quenched with sat. ammonium chloride solution (˜50 ml) and diluted with sat. sodium hydrogencarbonate solution (25 ml). The aqueous layer was extracted with diethylether (3×50 ml) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 5:1→1:1 petroleum/ether (40-60).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[Br:18][C:19]1[CH:20]=[C:21]([Br:43])[C:22]2[N:27]=[C:26]([C:28]3[N:29]([C:34]4[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH:30]=[C:31]([Br:33])[CH:32]=3)[O:25][C:24](=[O:41])[C:23]=2[CH:42]=1>O>[Br:33][C:31]1[CH:32]=[C:28]([C:26]([NH:27][C:22]2[C:21]([Br:43])=[CH:20][C:19]([Br:18])=[CH:42][C:23]=2[C:24]([N:4]([CH3:3])[NH:5][CH3:6])=[O:41])=[O:25])[N:29]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:30]=1
Reactant: CNNC
Reactant: O=c1oc(-c2cc(Br)cn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNN(C)C(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a mixture of 0.42 g of N,N′-dimethylhydrazine dihydrochloride, five drops of water, 0.87 g of potassium carbonate and 10 ml of tetrahydrofuran was added 0.59 g of 6,8-dibromo-2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one. The resulting mixture was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.52 g of 4-bromo-N-[4,6-dibromo-2-(N,N′-dimethylhydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH2:33]([SH:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>C(O)C>[CH2:1]([O:17][CH2:18][CH:19]([CH2:25][S:49][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(COCCCCCCCCCCCCCCCC)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCS
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOCC(CSCCCCCCCCCCCCCCCC)C(=O)OCC
Reaction time: 8 h

Procedure:
To a solution of 20 g of 2-[(hexadecyloxy)methyl]-2-propenoic acid, ethyl ester and 10 ml of triethylamine in 60 ml of ethanol is added 53 ml of hexadecyl mercaptan. This mixture is stirred overnight, then the solvents removed and the residue purified by HPLC [hexane:ethyl acetate (9:1)], to give 32.9 g of the desired compound as a white waxy solid.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: Fc1ccc(Br)c(OC2CCN(c3noc(-c4cn[nH]c4)n3)CC2)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cn1cc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)cn1

Procedure:
The title compound was prepared in a similar manner as described in Example 7 (step 4) from 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl]piperidine, sodium hydride and ethyl bromoacetate.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25][SH:26]>>[CH2:1]([N:5]1[C:9]2=[C:10]([S:26][CH2:25][C:19]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=3[Cl:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: Fc1cccc(Cl)c1CS
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(SCc3c(F)cccc3Cl)c21
Yield: 70.1 %

Procedure:
The title compound (cis/trans=18:82) was prepared as pale brown crystals in 70.1% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=(22/78) and 2-chloro-6-fluorophenylmethanethiol.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.O=P(Cl)(Cl)Cl.[C:20](=O)([O-])[O-:21].[K+].[K+]>CCO>[OH:13][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)[CH:12]=[CH:11][C:10]=1[CH:20]=[O:21]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N2CCNCC2)cc1O
Temperature: 5 °C

Procedure:
890 mg (5 mmol) 3-Piperazin-1-yl-phenol are suspended in 100 mL EtOH and treated with 0.42 mL (1 eq.) 12N HCl at a temperature below 10° C. The suspension is stirred an hour and slowly evaporated. The remaining beige powder is dried under high vacuum, then taken up in 60 mL DMF. The solution is cooled to 5° C. under argon, 0.503 mL (1.1 eq.) POCl3 added dropwise and the reaction mixture stirred for an hour at room temperature, then 30 minutes at 80° C., and finally allowed to cool to room temperature, upon which 2 g (3 eq.) solid potassium carbonate is added. The suspension is stirred 30 minutes at room temperature then evaporated, and the residue resuspended and stirred in a 1:1 mixture of dichloromethane and isopropanol. The suspension is filtered, the filtrate evaporated and dried to yield 600 mg crude 2-hydroxy4-piperazin-1-yl-benzaldehyde. This material is taken up in 40 mL of a 1:1 mixture of benzene and acetonitrile, 2.5 mL (5 eq.) piperidine and 683 mg (0.66 eq.) benzothiazol-2-yl-acetic acid methyl ester are added under argon and the reaction mixture refluxed for an hour. The product is extracted with dichloromethane and brine at 0° C., the combined organic phases dried with sodium sulphate, filtered and evaporated, then triturated with diisopropylether to yield 800 mg desired product (crude).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][S:8][CH:9]([CH2:21][CH2:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1C=CC=CC=1>[Cl:3][CH2:6][CH2:7][S:8][CH:9]([CH2:21][CH2:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCO)OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCCl)OC(C)=O

Procedure:
Thionyl chloride (13.1 g., 0.11 mole) is added dropwise with stirring to a solution of ethyl 8-(2-hydroxyethylthio)-12 -acetoxyheptadecanoate (43.2 g., 0.10 mole) in benzene (150 ml.). The solution is heated at reflux for 2 hours. Then, the solvent and excess thionyl chloride are removed by evaporation in vacuo to leave the title compound as an orange yellow residual oil.
Reaction SMILES: [P:1](Cl)([Cl:4])([Cl:3])=[O:2].[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:10]2.C(N(CC)CC)C>C(OCC)C>[Cl:3][P:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:10]2)([Cl:4])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](C)c1ccc2cc(O)ccc2c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)c1ccc2cc(OP(=O)(Cl)Cl)ccc2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
Phosphorus oxychloride (0.202 mL, 1 equiv) and (S)-methyl 2-(6-hydroxynaphthalen-2-yl)propanoate (Aldrich, 500 mg, 1 equiv) were stirred in anhydrous diethyl ether (25 mL). Anhydrous triethylamine was added (0.302 mL, 1 equiv) at −78° C. and the solution was allowed to warm to room temperature after 25 min, the triethylamine hydrochloride salt was filtered off and the solvent was removed under reduced pressure to give a clear pale yellow thick syrup (750 mg, 95%).