Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23](=[O:48])[CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:45][CH2:46][CH3:47])([CH3:21])([CH3:20])[CH3:19]>CC#N.CCOC(C)=O.O>[C:18]([O:22][C:23](=[O:48])[CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)(=[O:36])=[O:37])[CH2:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:45][CH2:46][CH3:47])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc2cc(N(CCCOc3ccccc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Phenoxypropyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>CO.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[N:23][OH:24])=[CH:11][CH:10]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(c2ccc(C=O)cc2)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1CN(c2ccc(C=NO)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
To a stirred suspension of 1-(4-formyl-phenyl)-azetidine-3-carboxylic acid methyl ester (Preparation 9, 2.6 g, 11.87 mmol) in methanol (25 mL) and water (25 mL) was added sodium acetate (1.75 g, 21.36 mmol) followed by hydroxylamine hydrochloride (1.24 g, 17.80 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 3 hours. After consumption of starting material, methanol was evaporated under reduced pressure and extracted with EtOAc (4×30 mL). Combined organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to afford yellow colored solid (2.86 g, 99%). 1H NMR (400 MHz, CDCl3) δ: 3.55-3.59 (m, 1H), 3.75 (s, 3H), 4.05-4.13 (m, 4H), 6.42 (d, 2H, J=8.56 Hz), 7.41 (d, 2H, J=8.6 Hz), 8.03 (s, 1H); LC-MS (M+H): =235.00.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
3-Cyanophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 min, the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1N HCl (30 mL) for 30 minutes and filtered. The solid was slurried with hot methanol (15 mL) to give 1-(3-cyano-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.33 g, 38%) as a white solid: mp 330-333° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.37-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.37-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 6.92 (t, J=5.5 Hz, 1H, NH), 7.32-7.65 (m, 6H, Ar), 7.93 (s, 1H, Ar), 9.00 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.55, 31.17, 39.67, 46.18, 51.57, 111.41, 118.91, 120.24, 121.59, 122.36, 124.64, 128.30, 130.02, 130.35, 131.63, 135.27, 139.92, 141.21, 154.98, 168.05, 171.00, 172.82; Anal. calcd. for C22H19N5O4+0.1H2O: C, 63.03; H, 4.62; N, 16.71. Found: C, 62.69, H, 4.48; N, 16.41.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=O)=[CH:7]1)[CH3:2].N1CCCCC1.[Cl-:26].[CH2:27]1[C:35]2[N+:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.C(OCC)(=O)C>C(O)(C)C>[Cl-:26].[CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[C:27]2[C:35]3[N+:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)=[CH:7]1)[CH3:2]
Reactant: c1cc[n+]2c(c1)CCC2
Reactant: CCN(CC)C(=O)Cn1cc(C=O)c2ccccc21
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCN(CC)C(=O)Cn1cc(C=C2CC[n+]3ccccc32)c2ccccc21
Reaction time: 24 h

Procedure:
0.800 g of N,N-diethyl-2-(3-formyl-1H-indol-1-yl)acetamide was solubilized in 4.2 ml of isopropanol. 0.238 g of piperidine was added, followed by 0.435 g of 2,3-dihydro-1H-indolizinium chloride dissolved in 7 ml of isopropanol. The reaction mixtures were brought to 80° C. for 24 h, with stirring. 50 ml of ethyl acetate were added in order to precipitate the dye. The precipitate was filtered off, and washed with 3 times with 25 ml of ethyl acetate before being dried under vacuum until a constant weight was obtained. 1.09 g of orange powder were recovered. The analyses were in conformity with the expected structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:14]([OH:33])([O:16][C@@H:17]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[C:18]([OH:20])=[O:19])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@H:17]([O:16][P:14]([C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:13])([OH:33])=[O:15])[C:18]([OH:20])=[O:19]
Reactant: C[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O[C@@H](CCCCN)C(=O)O
Reaction time: 2 h

Procedure:
A dichloromethane (0.5 ml) suspension of the (S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoic acid (3.1 mg) obtained in the above step (b) was added with anisol (0.05 ml) and trifluoroacetic acid (0.5 ml) at 0, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated, and the residue was washed with isopropyl ether to obtain trifluoroacetic acid salt of the title compound: (S)-6-amino-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoic acid (3.0 mg, 94%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Yield: 42.3 %

Procedure:
1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole was prepared by coupling of 1-benzyl-5-bromo-1H-indole (5.2 g, 18 mmol) and 4-trifluoromethoxyphenylboronic acid (4.7 g, 23 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.88 g, 1.1 mmol), and potassium carbonate (3.8 g, 27 mmol) in dioxane (135 mL) and water (13.5 mL) according to the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using hexane as an eluant yielded the title compound as a light yellow solid (2.8 g, 42%), mp: 62-63° C. 1HNMR (300 MHz, DMSO-d6): δ 7.85 (s, 1H), 7.75 (d, 2H, J=7.7 Hz), 7.5-7.6 (m, 2H), 7.4 (d, 3H, J=7.7 Hz), 7.2-7.35 (m, 5H), 6.6 (d, 1H, J=3.9 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=[O:9])(C)(C)C.[C:19]1([CH3:25])[CH:24]=CC=C[CH:20]=1.S(Cl)(Cl)=O.O[CH2:31][CH2:32][NH:33][C:34](=[O:52])[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][CH2:48][CH2:49][CH2:50][CH3:51]>N1C=CC=CC=1>[C:15]([CH:12]1[C:13]([C:19]([CH3:25])([CH3:24])[CH3:20])([OH:14])[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:31][CH2:32][NH:33][C:34](=[O:52])[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][CH2:48][CH2:49][CH2:50][CH3:51])=[O:9])=[CH:11]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCO
Reactant: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)NCCOC(=O)C1=CC(C(C)(C)C)C(O)(C(C)(C)C)C=C1

Procedure:
A mixture of 25 g (0.1 mole) 3,5-di-tert-butyl-4-hydroxybenzoic acid, 50 ml toluene and 8.5 ml thionyl chloride was refluxed for 3 hours. The excess thionyl chloride and the toluene were removed on a rotary evaporator. The acid chloride was dissolved in 50 ml toluene and was added to a mixture of 29.4 g (0.09 mole) N-(2-hydroxyethyl)stearamide, 20 ml toluene and 15 ml pyridine. The mixture was refluxed for two hours. The reaction mixture was then cooled, quenched with water, washed with dilute hydrochloric acid and with water. The toluene was removed by distillation, and the residue was crystallized from hexane. The title compound thus obtained melted at 56°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][S:12][C:11](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]3[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]3)[C:10]2=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC(OC(Cl)C)=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][S:12][C:11](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:10]2=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CCN(c2ccccc2C=C2SCCN(c3ccc(Cl)c(Cl)c3)C2=O)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C1C(=Cc2ccccc2N2CCNCC2)SCCN1c1ccc(Cl)c(Cl)c1

Procedure:
Under a nitrogen atmosphere, a mixture of 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one (338 mg, 0.756 mmol) in 9 mL of anhydrous 1,2-dichloroethane was treated with α-chloroethyl chloroformate (98 μL 0.907 mmol) and refluxed overnight. The solvent was then removed in vacuo and 10 mL of methanol was added and refluxed for 30 minutes. Following removal of the solvent, the residue was extracted into methylene chloride and washed with saturated aqueous sodium carbonate (Na2CO3) and saturated brine, dried with magnesium sulfate and concentrated to a foam. Flash chromatography using triethyl amine/methanol/ethyl acetate (1:2:97) gave the purified free base of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].C([Li])CCC.CCCCCC.CON(C)[C:24]([CH:26]1[CH2:28][CH2:27]1)=[O:25]>C1COCC1>[CH:26]1([C:24](=[O:25])[C:6]#[C:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH2:28][CH2:27]1
Reactant: CON(C)C(=O)C1CC1
Reactant: C#CC(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(C#CC(=O)C1CC1)OCC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
3,3-Diethoxy-1-propyne (10 mL, 70 mmol) was dissolved under argon in THF (150 mL) and cooled to −70° C. Then a 1.6 M solution of n-butyllithium in hexane (48 mL, 77 mmol) was added slowly at −70° C., then allowed to warm to −30° C. and stirred at −30° C. for 30 min, then cooled again to −70° C. Cyclopropanecarboxylic acid methoxy-methyl-amide (10 g, 77 mmol) was added at once at −70° C. (the temperature rose to −50°) then stirred without cooling until 0° C. was reached, then quenched with sat. NH4Cl solution (20 mL). Extraction: 2×AcOEt, 1× sat. NH4Cl, 1× sat. NaCl. The crude brown oil (15 g) was purified by chromatography on silica gel in heptane/ethyl acetate 10:1. One obtained 6 g (43%) of a yellowish oil. MS: m/z=151(M).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][O:26][CH:27]([CH3:30])[CH2:28][OH:29]>CO>[OH:29][CH2:28][CH:27]([O:26]/[N:25]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][N:14]=2)[N:17]=1)\[CH3:22])[CH3:30]
Reactant: CC(CO)ON
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl
Solvent: CO
Product: C/C(=N\OC(C)CO)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 44.3 %

Procedure:
A solution of 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (40 mg, 0.132 mmol) and 2-(aminooxy)propan-1-ol (intermediate Q) (33.6 mg, 0.264 mmol) in 15 mL of MeOH was stirred at it overnight. Solvent was evaporated and the crude was purified by HPLC (basic with 0.05% NH4OH) to give 22 mg (44%) of the title compound as a white solid. 1H-NMR (400 MHz, MeOH-4 δ ppm 8.82 (s, 1H), 8.33 (d, 1H), 8.12 (d, 1H), 7.98 (t, 3H), 7.84 (d, 1H), 7.55 (m, 1H), 4.84 (s, 2H), 4.50 (m, 1H), 3.72 (d, 2H), 2.32 (s, 3H), 1.33 (d, 3H). LC-MS (method B): [MH]+=377.0, tR=1.867 min.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][O:16][C:17](=[O:25])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1COCC1.[Cl:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]I>CCCCCCC.C(OCC)(=O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][O:16][C:17](=[O:25])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][Cl:33])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: ClCCCCCCI
Reactant: O=C(NCCOCCO)OCc1c2ccccc2cc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(NCCOCCOCCCCCCCl)OCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A 100 ml round bottom flask was charged with [2-(2-Hydroxy-ethoxy)-ethyl]-carbamic acid anthracen-9-ylmethyl ester (1.12 g, 3 mmol) and fresh sodium hydride, 60% dispersion in mineral oil (360 mg, 9 mmol) under inert atmosphere. 20 ml anhydrous THF was added and the reaction allowed to stir for 30 minutes. The flask is then cooled to between −10 and −20° C. by means of an ice/NaCl bath. When the temperature is reached 1-chloro-6-Iodohexane (1 ml, 6 mmol) is added via syringe. The reaction is maintained at ice/NaCl temperature for 2 hours, then slowly allowed to warm to room temperature overnight. At this point silica gel 60 is co-absorbed onto the reaction mixture with loss of solvent under reduced pressure. Silica gel chromatography takes place initially with heptane as eluent, followed by 10%, 20%, and 25% ethyl acetate. A total of 0.57 g (41% yield) of product is isolated from appropriate fractions: 1H NMR (CDCl3) δ 8.48 (s, H-10), 8.38 (d, H-1, 8), 8.01 (d, H-4, 5), 7.52 (dt, H-2, 3, 6, 7), 6.13 (s, CH2-anth), 5.29 (bs, exchangeable, NH), 3.74 (m, 4H), 3.55-3.15 (m, 8H), 1.84 (m, 4H), 1.61 (m, 1H), 1.43 (m, 1H), 1.25 (m, 2H). Mass spectrum, m/e Calcd for C26H32ClNO4.H2O: 475.21 (100%), 476.22 (29.6%). Found: 475.21, 476.52.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][CH2:17][CH2:18][C:19]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][CH:10]=2.C1CCCCC1>ClCCl>[ClH:3].[Cl:3][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][C:19]([CH2:18][CH2:17][CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][C:6]=2[F:5])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:21]1
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCN(CCO)CC1
Reactant: O=S(Cl)Cl
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCN(CCCl)CC1
Product: Cl
Temperature: 20 °C

Procedure:
1.2 cm3 of thionyl chloride in 5 cm3 of dichloromethane were added to a solution of 1.55 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-1-(2-hydroxy-ethyl)piperidine-4-carboxylate in 35 cm3 of dichloromethane, with stirring at a temperature in the region of 20° C. After stirring for 42 hours at a temperature in the region of 20° C., the reaction mixture was concentrated to dryness under reduced pressure (1.2 kPa) at about 50° C. The foam obtained was taken up in 3 times 100 cm3 of cyclohexane, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and oven-dried under reduced pressure (10 kPa) at a temperature in the region of 20° C. 1.8 g of ethyl 1-(2-chloroethyl)-4-[3-(3-fluoroquinolin-4-yl)propyl]piperidine-4-carboxylate monohydrochloride were obtained in the form of a cream-colored solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl>O>[CH3:32][O:31][C:27]1[CH:26]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[C:28]=1[O:29][CH3:30])[C:23]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:3]1)=[O:24]
Reactant: OC1CCN(CCc2c[nH]c3ccccc23)C1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)OC2CCN(CCc3c[nH]c4ccccc34)C2)cc(OC)c1OC
Reaction time: 24 h

Procedure:
A mixture of 3 g. (0.013 mole) of 3-[2-(3-hydroxypyrrolidinyl)ethyl]indole, 3 g. (0.013 mole) of 3,4,5-trimethoxybenzoyl chloride and 5 g. (0.05 mole) of sodium carbonate in 40 ml. of chloroform was stirred under anhydrous conditions for 24 hours. Then 0.3 g. of additional acid chloride was added and the mixture stirred another 24 hours. The mixture was treated with 50 ml. of water, stirred for 1 hour and the chloroform layer separated and dried over magnesium sulfate. Evaporation of the chloroform on a rotating evaporator gave an oil which would not crystallize.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12](=[S:15])[NH:13][N:14]=1.Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CCO.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:14][N:13]=[C:12]([S:15][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:11]=1
Reactant: BrCc1ccccn1
Reactant: COc1cc(C)ccc1-c1n[nH]c(=S)[nH]1
Agent: Br
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C)ccc1-c1nc(SCc2ccccn2)n[nH]1
Temperature: 60 °C
Yield: 72 %

Procedure:
To a solution of 5-(2-methoxy-4-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (Example 1a) (110 mg, 0.5 mmol) in 2 ml of EtOH was added 2-(bromomethyl)pyridine hydrobromide (152 mg, 0.6 mmol). The suspension was heated at 60° C. for 22 h. The reaction was diluted with EtOAc and washed with water, brine, dried over MgSO4 filtered and evaporated to produce an oil. The oil was purified on a preparative TLC plate to produce the desired product (72%). 1H NMR (500 MHz, CDCl3): δ 2.40 (s, 3H), 3.99 (s, 3H), 4.55 (s, 2H), 6.84 (s, 1H), 6.92-6.93 (d, 1H), 7.16-7.19 (dd, 1H), 7.53-7.55 (d, 1H), 7.62-7.65 (m, 1H), 8.15-8.17 (d, 1H), 8.56-8.57 (d, 1H). MS (M+H, 313).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]#[N:26])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:27]([Na])=[N+:28]=[N-:29].Cl>CS(C)=O.O.Br[Zn]Br>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12]([N:11]=3)=[CH:13][CH:14]=[C:15]([C:25]3[NH:29][N:28]=[N:27][N:26]=3)[CH:16]=4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: [N-]=[N+]=N[Na]
Reactant: CC(C)N(C)c1nc2cc(C#N)ccc2nc1-c1ccc2[nH]ncc2c1
Agent: Br[Zn]Br
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N(C)c1nc2cc(-c3nnn[nH]3)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of 2-(1H-indazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile (150 mg, 0.44 mmol) in DMSO (15 ml) was added dibromozinc (50 mg, 0.22 mmol), azidosodium (86 mg, 1.32 mmol), and water (2 ml), and the resulting mixture was stirred overnight at 130° C. in an oil bath. The solution was diluted with water (200 ml) and adjusted to pH 4 with HCl (2N), extracted with ethyl acetate (5×50 ml), dried over anhydrous magnesium, and concentrated in vacuo to give a residue, which was purified by a silica gel column (10% methanol in dichloromethane) to afford 3-(1H-indazol-5-yl)-N-methyl-N-(propan-2-yl)-7-(1H-tetrazol-5-yl)quinoxalin-2-amine as a yellow solid (38.5 mg, 23%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH:13]=O>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH:13]=[N:2][OH:3]
Reactant: NO
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1cc(Cl)cc(Cl)c1
Reaction time: 2 h

Procedure:
80 ml of ethanol were added to 23.82 g (342.8 mmol) of hydroxylamine hydrochloride. After addition of 28.12 g (342.8 mmol) of sodium acetate, a solution of 50.00 g (285.7 mmol) of 3,5-dichlorobenzaldehyde in 100 ml ethanol was added dropwise within a period of 30 min, the mixture was stirred for 2 h and then allowed to stand overnight. The reaction mixture was concentrated to dryness, 500 ml of CH2Cl2 were then added and the mixture was washed with 400 ml of water. The aqueous phase was washed once with 100 ml of CH2Cl2, the organic phase was dried over Na2SO4, filtered off and concentrated. The residue was used without further purification. Yield: 56.50 g (98%)
Reaction SMILES: [C:1]1([C:10]([OH:12])=[O:11])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[N:13]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[N:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>CC(C)=O>[N:14]([C:15]1[CH:16]=[CH:17][NH+:18]=[CH:19][CH:20]=1)=[N:13][C:21]1[CH:26]=[CH:25][NH+:24]=[CH:23][CH:22]=1.[C:1]1([C:10]([O-:12])=[O:11])[C:2]([C:7]([O-:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cc(N=Nc2ccncc2)ccn1
Reactant: O=C(O)c1ccccc1C(=O)O
Solvent: CC(C)=O
Product: O=C([O-])c1ccccc1C(=O)[O-]
Product: c1cc(N=Nc2cc[nH+]cc2)cc[nH+]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2-Benzenedicarboxylic acid, 1.66 g (0.01 mole) was added in one portion to a solution of 1.8 g (0.01 mole) of 4,4'-azodipyridine in 25 ml acetone. The reaction mixture was stirred at room temperature for one hour. The resultant suspension was filtered to leave an orange solid. Recrystallization from ethanol yielded 2.1 g of 4,4'-azodipyridinium-1,2-benzenedicarboxylate, having a m.p. of 171°-173° C.