Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:29])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4].[Mn]([O-])(=O)(=O)=[O:40].[K+]>CO.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:29])(=[O:40])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[N:11]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)=O)nc1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)nc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (301 mg, 0.55 mmol) in methanol (30 ml) was added a solution of potassium permanganate (88 mg, 0.55 mmol) in water (30 ml). The reaction mixture was stirred at 25° C. for 1 h. The suspension was filtered through a short silica gel pad and then washed with ethyl acetate (3×30 mL). The filtrate was concentrated and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (230 mg, 72%): LC/MS m/e calcd for C28H27N3O6S2 [M+H]+ 566.67, observed 565.9.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([O-:16])=O)=[CH:8][CH:7]=1.[Na+].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:30]=[C:29]([N:31]=[C:32]=[S:33])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:19][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:13]([CH3:18])([CH3:17])[C:14](=[O:16])[N:31]([C:29]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:22]([F:35])([F:21])[F:34])[CH:30]=3)[C:32]2=[S:33])=[CH:10][CH:11]=1
Reactant: CN(C)CCOc1ccc(NC(C)(C)C(=O)[O-])cc1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Agent: [Na+]
Product: CN(C)CCOc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 17 %

Procedure:
Compound 8 was prepared according to General Method 3. A mixture of sodium 2-(4-(2-(dimethylamino)ethoxy)phenylamino)-2-methylpropanoate (107 mg, 0.37 mmol) and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (107 mg, 0.44 mmol) was heated at 100° C. for 1 h then 82° C. for 12 h. The crude product was purified by silica gel chromatography using 100-200 Mesh silica gel (10% methanol in DCM) to obtain 30 mg of 4-(3-(4-(2-(dimethylamino)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. The product was converted its HCl salt by treating with ethanolic HCl, HPLC, Column: HYPERSIL GOLD C18, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 9.568 min, M+1, 477.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH:19]1([CH:22]([NH2:25])[CH2:23][CH3:24])[CH2:21][CH2:20]1>>[CH:19]1([CH:22]([NH:25][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[CH:5]=[CH:4][N:3]=2)[CH2:23][CH3:24])[CH2:21][CH2:20]1
Reactant: CCC(N)C1CC1
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Product: CCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 736.6 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.26 g, 0.86 mmol) and 1-cyclopropyl-propylamine (0.23 g, 1.71 mmol) were substantially as described in Part D of Example 9 to produce 2.32 g (100%) of crude (1-cyclopropyl-propyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine: MS (AP) m/z 366.2 [(M+H)+, 96].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: COCCCBr
Reactant: O=C1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCCOc1ccc2c(c1)C(=O)CCC2
Temperature: 80 °C
Reaction time: 23 h

Procedure:
To a solution of 7-hydroxy-1-tetralone (4.05 g) in acetonitrile (75 mL) were added 1-bromo-3-methoxypropane (4.59 g), potassium iodide (415 mg) and potassium carbonate (5.18 g), and the mixture was heated to stir at 80° C. for 23 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with n-hexane to give 7-(3-methoxypropoxy)-3,4-dihydronaphthalen-1(2H)-one [REx(12-1)] (4.70) as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[N-:19]=[N+:20]=[N-:21].[Na+].CN(C)C=O>O>[N:19]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[N+:20]=[N-:21]
Reactant: Cc1ccc(-c2c(Cl)ncnc2OCCO)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2c(N=[N+]=[N-])ncnc2OCCO)cc1
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of 2-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (21.85 g), sodium azide (10.7 g) and dimethyformamide (260 ml) is heated with stirring at 75°-80° C. overnight. After cooling, the mixture is treated with water, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is crystallized from hexane to give 2-{6-azido-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (19.6 g).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][C@@:14]1([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[O:19][C:18](=[O:20])[N:17]([C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32](=[O:35])[NH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH3:22])[CH2:16][CH2:15]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:43]I>C1COCC1>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][C@@:14]1([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[O:19][C:18](=[O:20])[N:17]([C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][C:32](=[O:35])[N:31]([CH3:43])[CH:30]=3)=[CH:27][CH:28]=2)[CH3:22])[CH2:16][CH2:15]1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: CI
Reactant: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a suspension of NaH (18 mg, 0.72 mmol) in THF (0.5 mL) was added a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 0.18 mmol) in THF (10 mL) at 0° C. The resulting mixture was stirred for 1 h. Then CH3I (613 mg, 43.2 mmol) was added, and the mixture was stirred for 3 h. The reaction was quenched with aq NH4Cl solution. The organic phase was separated, and concentrated to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (104 mg, 100%), which was used for the next step without further purification. Step 6
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][CH2:9][C:10]1([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)=O>[CH:5]([NH:8][CH2:9][C:10]1([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7]
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CN1CCN(C2(CNC=O)CCCCC2)CC1
Reaction time: 1 h
Yield: 62.7 %

Procedure:
Formic acid (6.9 g, 0.15 mole) and acetic anhydride (15.3 g, 0.15 mole) were mixed without cooling and kept at room temperature for 1 hr. 1-(1-aminomethylcyclohexyl)-4-methylpiperazine (8.4 g, 0.04 mole) was dissolved in formic acid (12 ml) and the formylating mixture (16 ml) added. This produced vigorous effervescence and a rise in temperature to 70°. The mixture was left at room temperature for 2 hr. and then heated on a water bath at 55° for 0.75 hr. The solvents were removed under reduced pressure yielding a viscous brown oil (6.0 g, 66.3%) which crystallised as colourless plates of 1-(1-formylaminomethylcyclohexyl)-4-methylpiperazine from light petroleum (b.p. 80°-100°), m.p. 97°-98°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[NH:19][C:20]1[N:24]([CH2:25][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[N:21]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].O1[CH2:54][CH2:53][O:52][CH2:51]C1>O>[Si:29]([O:28][CH2:27][CH2:26][CH2:25][N:24]1[C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[N:21]=[C:20]1[NH:19][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:4]3[CH:8]=[N:7][CH:11]=[CH:54][C:53]=3[O:52][CH3:51])[CH:3]=2)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=1)([C:32]([CH3:34])([CH3:35])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1c(Nc2nn(COCC[Si](C)(C)C)c3ccc(Br)cc23)nc2ccccc21
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3ccccc3n1CCCO[Si](C)(C)C(C)(C)C)nn2COCC[Si](C)(C)C
Temperature: 110 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of 5-bromo-N-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-benzo[d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-amine (from Step 1: 191 mg, 0.000303 mol), 4-methoxypyridin-3-yl-3-boronic acid (64 mg, 0.00042 mol) and (1,1′-bis(diphenylphosphino)-ferrocene)dichloropalladium(II), complexed with dichloromethane (1:1) (41 mg, 0.000050 mol), was dissolved in 1,4-dioxane (3.04 mL). To this mixture was added 2.0 M sodium carbonate in water (0.76 mL) with stirring. The mixture was flushed with argon sealed and heated at 110° C. After 3 hours, the mixture was diluted with methylene chloride, washed with water and brine, the organic phase dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in methylene chloride and purified by flash chromatography (50-100% ethyl acetate-0.3% triethylamine in hexanes) to give 132 mg (66%) of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[S:49]1[CH:53]=[CH:52][C:51]([C:54]2[N:55]=[CH:56][C:57]([NH2:60])=[N:58][CH:59]=2)=[CH:50]1.N1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:60][C:57]2[CH:56]=[N:55][C:54]([C:51]3[CH:52]=[CH:53][S:49][CH:50]=3)=[CH:59][N:58]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1cnc(-c2ccsc2)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3ccsc3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
A solution of triphenylphosphine (149.0 mg, 0.568 mmol) in methylene chloride (8 mL) cooled to 0° C. was treated with N-bromosuccinimide (103.0 mg, 0.579 mmol). The reaction mixture was stirred at 0° C. for 5 min and then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 150.0 mg, 0.453 mmol). The reaction mixture was allowed to warm to 25° C. over 15 min. The reaction mixture was then treated with 5-thiophen-3-yl-pyrazin-2-ylamine (168.0 mg, 0.948 mmol) followed by pyridine (0.16 mL, 1.978 mmol). The resulting reaction mixture was stirred at 25° C. for 1.5 h. The reaction mixture was then diluted with methylene chloride and washed with a dilute aqueous hydrochloric acid solution. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 to 2/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-thiophen-3-yl-pyrazin-2-yl)-propionamide (105.6 mg, 47.5%) as a pale yellow foam: mp 96–102° C. (foam to gel); (ES)+-HRMS m/e calcd for C23H24ClN3O3S2 (M+H)+ 490.1021, found 490.1023.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
A mixture containing 325 g of 4-cyanophenol, 346 mL of benzyl chloride and 758 g of potassium carbonate in 1.2 L of NMP was heated at 95° C. with stirring for 1.5 hrs. The reaction mixture was cooled to room temperature and poured into 5L of cold water. The resulting white solid was collected, washed with water and hexanes and dried at 70° C. in vacuo giving 570.0 g of 4-benzyloxybenzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:37]([N:40]([CH2:46][CH2:47][CH3:48])[C@H:41]([C:43](O)=[O:44])[CH3:42])[CH2:38][CH3:39]>C1COCC1.C(OCC)(=O)C>[CH3:42][C@H:41]([N:40]([CH2:37][CH2:38][CH3:39])[CH2:46][CH2:47][CH3:48])[C:43]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1)=[O:44]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: CCCN(CCC)[C@@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)[C@@H](C)C(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 41.7 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.8 g, 4.12 mmol) in THF (200 mL) was added EDC hydrochloride (2.37 g, 12.4 mmol), HOBT (1.67 g, 12.4 mmol), and N,N-dipropyl-L-alanine (2.14 g, 12.4 mmol). After stirring at rt for 5 days, the reaction was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (200 mL) and 1M NaOH (200 mL). The organic layer was separated, adsorbed onto silica gel, and purified by column chromatography (DCM to 5% MeOH/DCM) to provide N-{(1S)-1-methyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-N-propyl-1-propanamine (0.6 g, 42%). ESIMS (M+H)+=350.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:21]>C(Cl)(Cl)Cl>[O:21]1[C:2]2([CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH2:3]2)[CH2:1]1
Reactant: C=C1CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CC2(CO2)C1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
To a solution of phenylmethyl 3-methylideneazetidine-1-carboxylate (2.46 g, 0.0121 mol) in chloroform (100 mL) was added 3-chloroperoxybenzoic acid (12.5 g, 0.0726 mol) at 0° C. The reaction mixture was allowed to warm up to room temperature over a period of 12 hours then quenched with 1 M sodium thiosulfate/saturated aqueous sodium:bicarbonate (1:1). The layers were separated and the organic layer was dried over anhydrous magnesium sulfate then concentrated. The residue was purified by flash chromatography (5-15% ethyl acetate in hexanes) to afford phenylmethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (2.2 g, 83% yield) as clear and colorless oil. 1H NMR (400 MHz, CDCl3): 7.37-7.29 (m, 5H), 5.12 (s, 2H), 4.35-4.26 (m, 4H), 2.85 (s, 2H). MS (EI) for C12H13NO3: 220 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:4].[Br:25]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(Oc3ccc(OC)cc3)cccc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2c(Oc3ccc(OC)cc3)cccc2c1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.2 %

Procedure:
A mixture of 4-hydroxy-8-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (1.17 mmol, 381 mg), N-bromosuccinimide (1.3 mmol, 234 mg), benzoyl peroxide (0.06 mmol, 15 mg), and CCl4 (8 mL) was refluxed with stirring for 2.5 h. After cooling to ambient temperature silica gel was added and the mixture was concentrated in vacuo. The residue was added on top of a chromatography column filled with silica gel. Elution with CH2Cl2 gave the title compound as a tan solid (403 mg); MS-(+)-ion: M+1, 79Br/81Br=404.3 and 406.3.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13]OC(=O)C)[CH:11]=2)[CH:6]=[N:5]1)(=O)C.[BrH:18]>>[Br:18][CH2:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[N:5][NH:4]2)=[CH:8][CH:9]=1
Reactant: Br
Reactant: CC(=O)OCc1ccc2cnn(C(C)=O)c2c1
Product: BrCc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
A suspension of 1-acetyl-6-(acetoxymethyl)indazole (9.5 g, 41 mmol) (4-4) in aqueous hydrobromic acid (48% aqueous solution, 20 mL, 177 mmol) was stirred at room temperature for 46 hours. The solid was collected on a Buchner funnel and dried under vacuum for 12 hours. The filtrate was stirred at room temperature for additional 24 hours and more solid was collected. After drying under vacuum, title compound was obtained as a yellow solid (10.0 g, 84%) which was used as such without further purification. MS (electrospray) 211 (M+1 for 79Br), 213 (M+1 for 81Br); 1H N MR (CDCl3) δ 4.85 (s, 2H), 7.65 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J 8.4 Hz), 8.05 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].O.Cl>CO>[N:15]1([CH:12]2[CH2:13][C:14]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][CH2:11]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1cccc2c1CC(N1CCCCCC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2c1CC(N1CCCCCC1)CC2
Temperature: 75 °C

Procedure:
A mixture of 1.56 g 7-(1-Hexahydroazepinyl)-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester, 1.57 mL 12 N NaOH, 1.57 mL water in 10 mL methanol was refluxed (70-80° C.) overnight. TLC showed no starting material remaining. The mixture was neutralized with 6 N HCl to pH 5-6 and concentrated to dryness using toluene and methanol. A white solid was recovered and used crude.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([Si](C=[N+]=[N-])(CC)CC)C>C(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:32])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Si](C=[N+]=[N-])(CC)CC
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Yield: 29.1 %

Procedure:
A solution of 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (100 mg, 0.24 mmol) in 15 ml DCM was cooled to 0° C. under argon atmosphere, followed by the addition of triethylsilyldiazomethane (0.12 ml, 0.24 mmol). The run was quenched with 1 ml water and all the solvents were evaporated under vacuum. Methyl 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoate (30 mg, 30%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes), and its hydrochloride was made by bubbling HCL gas in ether solution. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.31-3.68 (m, br, 11H), 4.42 (s, 2H), 6.06 (d, J=1.8 Hz, 1H), 6.25 (dd, J=1.8, 9.1 Hz, 1H), 7.26-7.48 (m, 10H), 7.64 (d, J=9.1 Hz, 1H), 8.06 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 46.1, 51.0, 95.3, 100.4, 102.8, 127.0, 127.4, 128.4, 128.5, 129.6, 132.4, 135.7, 139.3, 151.7, 154.6, 167.8, 169.1.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12](Cl)[C:13]([O:15]CC)=O)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[NH2:19][C:20]([NH2:22])=[S:21].C([O-])(=O)C.[Na+]>COCCO>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]2[S:21][C:20](=[NH:19])[NH:22][C:13]2=[O:15])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCOC(=O)C(Cl)Cc1ccc(CC(C)=O)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: CC(=O)Cc1ccc(CC2SC(=N)NC2=O)cc1
Temperature: 100 °C

Procedure:
A mixture of ethyl 3-(4-acetonylphenyl)-2-chloropropionate, ethylene ketal (4.86 g), thiourea (1.19 g) and sodium acetate (1.29 g) in 2-methoxyethanol (25 ml) was stirred and heated at 100 ° C. for 16 h. The solvent was evaporated and the residue was diluted with 50:50 water/hexane (50 ml). The resulting solid was filtered, dried and purified by chromatography on silica gel. Elution with methanol:chloroform (4:96) gave 5-(4-acetonylbenzyl)-2-iminothiazolidine-4-one as a white solid, mp 196°-198° C.
Reaction SMILES: Br[CH:2]([CH3:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[Na+].[I-:11]>CC(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][CH2:9][I:11]
Reactant: COC(=O)CCC(C)Br
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CCCCI
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To a solution of methyl 4-bromovalerate (14 g) in acetone (63 mL), NaI (11.5 g) was added and the mixture was refluxed for 2 hr. It was then cooled to r.t. and the precipitate was filtered. The filtrate was evaporated and ether was added to the residue. The resulting suspension was filtered and the ethereal phase washed with 5% aq NaHSO3 (3×100 mL) and with brine (1×100 mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated to give the crude title compound as a yellow oil (15.85 g).