Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[NH2:31][C:32]([NH2:34])=[O:33].Cl>CCO>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1cccnc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccnc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 21 %

Procedure:
A mixture of 2-phenyl-1-(pyridin-3-yl)ethanone (Intermediate 31) (110 mg, 0.56 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (107 mg, 0.51 mmol), urea (91 mg, 1.52 mmol), and concentrated HCl solution (0.04 mL, 0.56 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo and purified by preparative HPLC to give Compound 65 (46.21 mg, yield 21%). 1H NMR (DMSO-d6 400 MHz): δ 10.28 (s, 1H), 8.91 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.36 (s, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.36 (t, J=5.2 Hz, 1H), 7.15 (s, 1H), 7.09-7.04 (m, 3H), 6.86 (d, J=6.8 Hz, 2H), 5.29 (d, J=2.0 Hz, 1H), 4.04 (q, J=6.8 Hz, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 433.0 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=S)([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH2:24][CH:25]([OH:31])[C:26]([O:29][CH3:30])([CH3:28])[CH3:27].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=[N:23][CH2:24][CH:25]([OH:31])[C:26]([O:29][CH3:30])([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(C)(C)C(O)CN
Reactant: C[C@H]1NC(=S)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Agent: Cl[Hg]Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(C)(C)C(O)CN=C1N[C@H](C)[C@H](c2ccccc2)C[C@@H]1NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl[(3S,5S,6R)-6-methyl-5-phenyl-2-thioxopiperidin-3-yl]carbamate (150 mg, 0.47 mmol) in ethanol (4.7 mL) was added 1-amino-3-methoxy-3-methylbutan-2-ol (156 mg, 1.17 mmol), mercury (II) chloride (165 mg, 0.61 mmol), and triethylamine (163 μL, 1.17 mmol). The mixture was stirred 20 min, and then concentrated, giving the crude title compound. MS 420.4 (M+1).
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[C:5]([N+:24]([O-:26])=[O:25])=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH2:8][CH:9]([OH:20])[CH2:10][NH:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13].[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4]1[C:5]([N+:24]([O-:26])=[O:25])=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH2:8][C:9](=[O:20])[CH2:10][N:11]([C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:27](=[O:29])[CH3:28]
Reactant: COc1cccc(OCC(O)CN[C@H](C)c2ccccc2)c1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(OCC(=O)CN(C(C)=O)[C@H](C)c2ccccc2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from Example 7B (33.0 g, 77.6 mmol) in dichloromethane (600 mL) at 0 ° C. was treated sequentially with acetyl chloride (6.4 g, 81.0 mmol) and triethylamine (23.6 g,233 mmol) in dichloromethane (50 mL), stirred for 1 hour at 0° C., and quenched with 1M NaOH. The organic layer was washed with brine, dried (MgSO4), and concentrated to provide the title compound. 1H NMR (300 MHz, CDCl3) δ1.60 (d, 3H), 2.29 (s, 3H), 3.70 (d, 1H),3.86 (s, 3H), 4.14 (d, 1H), 4.55 (d, 1H), 4.73 (d, 1H), 5.15 (q, 1H), 6.55 (d, 1H), 6.65 (d, 1H), 7.20-7.42 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].Cl[C:11]1[C:16]2[CH:17]=[N:18][C:19]3[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=3[C:15]=2[N:14]2[N:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:13]2[N:12]=1>C1C=CC=CC=1>[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][O:8][C:11]1[C:16]2[CH:17]=[N:18][C:19]3[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=3[C:15]=2[N:14]2[N:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:13]2[N:12]=1
Reactant: CN(C)CCCO
Reactant: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1cnn2c1nc(OCCCN(C)C)c1cnc3c(cnn3CC)c12
Reaction time: 10 h

Procedure:
To a suspension of 3.6 g of sodium hydride in 100 ml of dry benzene 15.3 g of 3-(dimethylamino)propanol are added dropwise at reflux temperature with stirring. Heating is continued for 10 hours. After this time, 34.4 g of 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester are added and the solution is refluxed for 5 additional hours. The solution is evaporated to dryness and the residue is treated with water, filtered off and recrystallized from ethyl acetate. 12 g of 5-[3-(dimethylamino)propoxy]-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester are obtained (29.3%); m.p. 106°-107°.
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:25]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:26]([C:31]([NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[C:36]([Cl:43])[CH:35]=2)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.O>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:38]([C:37]3[CH:41]=[CH:42][C:34]([NH:33][C:31]([C:26]4[C:25]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:32])=[CH:35][C:36]=3[Cl:43])=[O:39])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Reactant: c1cnc2c(c1)CNc1ccccc1O2
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3cccnc3Oc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.198 g of 5,6-dihydropyrido[2,3-b][1,5]benzoxazepine, 0.155 g of N,N-diisopropylethylamine and 0.444 g of 4-[([1,1-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride in 12 ml of dichloromethane is stirred at room temperature for 2.5 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N Na2CO3, H2O, brine and dried (Na2 SO4). The solution is passed through a thin pad of hydrous magnesium silicate. The filter pad is washed with 50 ml of hexane-ethyl acetate (1:2) and the filtrate concentrated to dryness.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[CH3:25][N:26]([CH3:43])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]#[C:36][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[OH:34])=[CH:29][CH:28]=1.CN(C)C1C=CC(C(C#C)O)=CC=1>C(OCC)C>[CH3:43][N:26]([CH3:25])[C:27]1[CH:28]=[CH:29][C:30]([C:33](=[O:34])[C:35]#[C:36][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:31][CH:32]=1
Reactant: CN(C)c1ccc(C(O)C#Cc2ccncc2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: C#CC(O)c1ccc(N(C)C)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)c1ccc(C(=O)C#Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place pyridinium dichromate (1.75 g) and methylene chloride (20 mL) under argon atmosphere and cool to 0° C. Add a 1:1 mixture of 4-dimethylamino-α-[(4-pyridinyl)ethynyl]-benzenemethanol and 4-dimethylamino-α-(ethynyl)-benzenemethanol (0.8 g). Stir overnight while slowly warming to room temperature. Dilute with ethyl ether and filter the chromium salts. Purify by silica gel chromatography (2:1 ethyl acetate/hexane) to yield 0.94 g of the title compound; mp 143°-145° C.
Reaction SMILES: [CH:1]1([C:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:24]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH:1]1([C:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([NH:29][C@H:26]2[CH2:27][CH2:28][N:24]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)C(O)(c1ccccc1)C1CCCC1
Temperature: 2.5 °C
Reaction time: 19 h
Yield: 95 %

Procedure:
The compound 2-cyclopentyl-2-hydroxy-2-phenylacetic acid (0.52 g, 2.36 mM) and (3S)-1-benzyl-3-aminopyrrolidine (0.5 g, 2.84 mM) were dissolved in dimethylformamide (10.0 ml) and N-methylmorpholine (1.3 ml, 11.8 mM) was added into it followed by the addition of 1-hydroxybenzotriazole (0.32 g, 2.36 mM) at 0-5° C. The reaction mixture was maintained at 0-5° C. for 1 hour and then at room temperature for 19 hours. The reaction mixture was poured into water (100.0 ml) with constant stirring. The organic compound was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate water and brine solution followed its drying and concentration over anhydrous sodium sulphate. The residue was purified by silica gel column chromatography using 10% methanol in chloroform to get the title compound. Yield=95% (0.5 g, 2.38 mM).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][Mg]I>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:17]([OH:18])[CH3:22])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Mg]I
Reactant: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C

Procedure:
3-[2(E)-(7-Chloroquinolin-2-yl)ethenyl}benzaldehyde (Example 6a part i) (2.44 g, 8.3 mmol) in dry THF (75 ml) was cooled in an ice bath under nitrogen and stirred as 1M methyl magnesium iodide in diethyl ether (9.9 ml) was added over 5 minutes. The reaction was stirred at 0° C. for half an hour, warmed to room temperature and quenched with water. The mixture was extracted into ethyl acetate, the combined organic extracts dried, filtered and evaporated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14]Br.[H-].[Na+].CC(O)C>CS(C)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([C:7]#[N:8])[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chlorobenzyl cyanide (10 g) and 1,3-dibromopropane (7.5 ml) in dry dimethyl sulphoxide (12 ml) was added dropwise under nitrogen to a stirred mixture of sodium hydride (3.6 g) dispersed in mineral oil (3,6 g) and dimethylsulphoxide (70 ml) at a temperature in the range 30° to 35° C. The mixture was stirred at room temperature for two hours and then propan-2-ol (10 ml) and water (150 ml) were added dropwise. The mixture was filtered through a diatomaceous earth sold under the Registered Trade Mark CELITE and the solid residue washed with ether. The filtrate was extracted with ether and the ether phases combined, washed with water, dried and evaporated. 1-(4-chlorophenyl)-1-cyclobutanecarbonitrile (b.p. 116°-120° at 0.6 mm Hg) was isolated by distillation. This method is a modification of that described by Butler and Pollatz (J.Org.Chem., Vol. 36, No. 9, 1971, p. 1308).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:52][C:53]1[S:54][C:55]2[CH:61]=[CH:60][CH:59]=[CH:58][C:56]=2[N:57]=1.C(N(CC)CC)C>C(Cl)Cl>[S:54]1[C:55]2[CH:61]=[CH:60][CH:59]=[CH:58][C:56]=2[N:57]=[C:53]1[NH:52][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 30, 182 mg, 0.50 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), and 2-aminobenzothiazole (113 mg, 0.75 mmol) in methylene chloride (10 mL) at 25° C. was treated with triethylamine (0.21 mL, 1.50 mmol). The reaction mixture was stirred at 25° C. for 48 h. The reaction mixture was then diluted with methylene chloride (25 mL) and washed with a 3N aqueous hydrochloric acid solution (1×25 mL), water (1×25 mL), and a saturated aqueous sodium chloride solution (3×25 mL). The organic layer was dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 70/30 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide (205 mg, 82.6%) as a white solid: mp 105-110° C.; EI-HRMS m/e calcd for C23H23F3N2O3S2 (M+) 496.1102, found 496.1102.
Reaction SMILES: [CH2:1]([C:3]1([CH2:32][CH3:33])[C:6](=[O:7])[N:5]([C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])=[O:9])[CH:4]1[O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C([Cl:42])=O>C(Cl)Cl>[CH2:1]([C:3]1([CH2:32][CH3:33])[C:6](=[O:7])[N:5]([C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])=[O:9])[CH:4]1[O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([Cl:42])=[O:28])=[CH:25][CH:24]=1)[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)O)cc1)c1ccc(C)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)Cl)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.150 g of [S-(R*,S*)] 4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)-carbonyl)-4-oxo-2-azetidinyl)oxy)benzoic acid in 5 ml methylene chloride containing a catalytic amount of dimethylformamide is added 0.5 ml of oxalyl chloride. The mixture is stirred at room temperature for 30 minutes and then concentrated in vacuo to yield (S-(R*,S*))-4-((3,3-diethyl-1-((1-(4-methyl-phenyl)-butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)-benzoyl chloride.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19]N.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:19]2[C:14]3[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=3[C:24]3[CH2:23][N:22]([CH3:21])[CH2:27][CH2:26][C:25]2=3)=[CH:5][CH:6]=1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccccc1Cl
Reactant: Fc1ccc(CCBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cccc(Cl)c3n2CCc2ccc(F)cc2)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-4-fluorobenzene, 2-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:41]4[CH2:42][CH2:43][N:38]([C:33]5[N:32]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH2:39][CH2:40]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ncccn2)CC1

Procedure:
(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-pyrimidinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=593.97 (M+H+); retention time=0.84 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21]C1C(OC)=CC=CC=1C=O>>[CH3:1][O:2][C:3]1[C:8]([O:21][CH3:20])=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Reactant: COc1cccc(C=O)c1OC
Product: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1OC
Yield: 86 %

Procedure:
According to the preparation of 42, 2,3-dimethoxybenzaldehyde (36) (1.2 g, 7.3 mmol) was used to afford 45 (1.8 g, 86.0%) as pale yellow needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[Cl:17][C:18]1[C:23]([CH2:24]Cl)=[CH:22][N:21]=[C:20]2[N:26]([CH2:29][CH3:30])[N:27]=[CH:28][C:19]=12.C>O1CCCC1>[ClH:1].[Cl:17][C:18]1[C:23]([CH2:24][O:16][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:22][N:21]=[C:20]2[N:26]([CH2:29][CH3:30])[N:27]=[CH:28][C:19]=12
Reactant: CCn1ncc2c(Cl)c(CCl)cnc21
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CCn1ncc2c(Cl)c(COC(Cn3ccnc3)c3ccc(Cl)cc3Cl)cnc21
Product: Cl
Reaction time: 2 h

Procedure:
7.71 g. of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-ethanol (0.03 mol.) and 6.9 g. of 4-chloro-5-chloromethyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine (0.03 mol.) are reacted according to the procedure of Example 1b. The combined tetrahydrofuran layers are treated with charcoal and filtered. Addition of 250 ml. of ether to the tetrahydrofuran solution separates an oily impurity which is removed by decanting the solution. After the solution containing the free base is cleared up by the addition of Hyflo filter aid there is added an excess of ethereal hydrochloric acid. The precipitated hydrochloride is allowed to stand for 2 hours, then filtered off, washed with ether and dried in a vacuum desiccator, yield: 8.3 g. (61%). The product is recrystallized from 3 N-hydrochloric acid with charcoal. The so obtained 4-chloro-5-[[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy]methyl]-1-ethyl-1H-pyrazolo[3,4-b]-pyridine, hydrochloride (1:1) contains half a mole of water; m.p. 166°-167°.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:27])[CH2:25]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:22][O:23][C:24](=[O:27])[CH2:25][CH:8]([C:6]1[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(Br)ccc2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(c1nc(Br)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of 6-bromo-3-nitro-2-(toluene-4-sulfonylmethyl)-pyridine (3.3 g, 9.0 mmol), bromo-acetic acid methyl ester (2.1 mL, 22.5 mmol) and K2CO3 (8.4 g, 60.8 mmol) were suspended in DMF (18.0 mL) and stirred at 40° C. for 1 hour before pouring into water (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 3-(6-bromo-3-nitro-pyridin-2-yl)-3-(toluene-4-sulfonyl)-propionic acid methyl ester (3.9 g, quant.) as a light yellow solid. MS: 443.1 & 445.1 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:58]=[CH:57][C:8]([CH2:9][N:10]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([O:55]C)=[O:54])=[CH:49][CH:48]=2)[C:11](=[O:46])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:21]=[C:20]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:19]=2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].C(C1C=CC(N(C2C=CC(C(O)=O)=CC=2)C(=O)CCCCCOC2C=C(OCCCCCCCCCC)C=C(OCCCCCCCCCC)C=2)=CC=1)(O)=O>C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([C:47]2[CH:48]=[CH:49][C:50]([C:53]([OH:55])=[O:54])=[CH:51][CH:52]=2)[C:11](=[O:46])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:21]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]=2)=[CH:57][CH:58]=1)([OH:4])=[O:2]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(OCCCCCC(=O)N(Cc2ccc(C(=O)OC)cc2)c2ccc(C(=O)OC)cc2)c1
Agent: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(OCCCCCC(=O)N(c2ccc(C(=O)O)cc2)c2ccc(C(=O)O)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(OCCCCCC(=O)N(Cc2ccc(C(=O)O)cc2)c2ccc(C(=O)O)cc2)c1
Yield: 80.3 %

Procedure:
Compound 20b (443 mg, 0.552 mmol) in THF (14 ml) is treated with an aqueous solution of LiOH (0.5 M, 3.31 ml, 1.66 mmol) in accordance with the production of compound 2a. 343 mg (80%) of the desired dicarboxylic acid 2b are obtained as a colorless resin. IR (KBr) 3030, 2890, 2820, 2640, 2520, 1700, 1655, 1575 cm−1; 1H-NMR (CDCl3) δ 8.08 (d, 8.6 Hz, 2H), 8.01 (d, 8.4 Hz, 2H), 7.29 (d, 8.4 Hz, 2H), 7.10 (d, 8.6 Hz, 2H), 6.05 (t, 1.9 Hz, 1H), 6.02 (d, 1.9 Hz, 2H), 5.01 (s, 2H), 3.92-3.83 (m, 6H) 2.16 (t, 7.4 Hz, 2H), 1.80-1.62 (m, 8H), 1.49-1.21 (m, 30H), 0.87 (t, 6.7 Hz, 6H); MS (FD) m/z (%) 774 (M+). Anal. calc. for C47H67NO8: C, 72.93; H, 8.72; N, 1.81. Found C, 72.65; H, 8.77; N, 1.77.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9]CCC.S(=O)(=O)(O)[OH:14]>>[CH2:1]([OH:14])[CH:2]([OH:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C=CCCCCCC
Reactant: CC(C)=O
Reactant: O=S(=O)(O)O
Product: CCCCCCC(O)CO

Procedure:
A homogeneous clear solution is prepared by adding 3 moles of acetone to 1 mole of octene (1,2) oxide at room temperature. After adding 50 grams of 5% aqueous sulfuric acid to the solution, the acetone is evaporated off and the resulting solution is neutralized by adding an aqueous sodium hydroxide. The neutralized solution is extracted with pet ether and the extract dried over anhydrous magnesium sulfate. The pet ether is stripped off and 1,2-octanediol is obtained by distilling under vacuo, b.p. 103°-105°C/0.2 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]3=[CH:19][CH:20]=[CH:21][N:8]3[CH2:7][C:6]=2[CH:22]=1.[Cl:23]N1C(=O)CCC1=O>O1CCCC1>[Cl:23][C:21]1[N:8]2[C:9]([CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[O:11][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[CH2:7]2)=[CH:19][CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCC(C2Oc3ccc(Cl)cc3Cn3cccc32)CC1
Solvent: C1CCOC1
Product: CN1CCC(C2Oc3ccc(Cl)cc3Cn3c(Cl)ccc32)CC1

Procedure:
A solution of 7-chloro-11-[(1-methyl)piperidin-4-yl]5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (4.0 g; 0.013 mole) and N-chlorosuccinimide (2.0 g; 0.015) mole in 150 ml of tetrahydrofuran was heated at reflux for 4.5 hours.