Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[S:24]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]12>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:32]([C:29]3[N:26]4[C:25]([S:24][CH:28]=[CH:27]4)=[N:31][CH:30]=3)=[O:33])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cnc2sccn12
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cnc4sccn34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.74 min; [M+H]+=483.0.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:11][CH2:12][OH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:13][CH2:12][CH2:11][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: c1ccc2c(c1)CNC2
Reactant: OCCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCCN1Cc2ccccc2C1
Yield: 62.7 %

Procedure:
A solution of 2.85 g (0.0252 mol) of isoindoline, 2.99 g (0.0252 mol) of 2-bromoethanol and 5.09 g (0.05 mol) of triethylamine in 100 ml of dry toluene was refluxed for 12 hours. After cooling the mixture was filtered, concentrated in vacuo, dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield 2.58 g (63%) of a dark red oil. NMR: (CDCl3) δ 2.78 (2H, t), 3.52 (2H, t), 3.82 (4H, s), 7.0 (4H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][C:4]=1[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1CCl.[CH3:30][N:31]([CH3:34])C=O>>[N:31]1[CH:34]=[CH:5][C:4]([CH:12]([O:10][C:9](=[O:11])[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:12]([OH:14])=[O:13])[CH:5]=2)[C:25]2[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=2)=[CH:3][CH:30]=1
Reactant: ClCc1ccccn1
Reactant: CN(C)C=O
Reactant: COc1ccc(C(=O)O)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)OC(c2ccncc2)c2ccncc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
In N,N-dimethylformamide (“DMF”) (25 mL) was stirred 4-methoxy-1,3-benzenedicarboxylic acid (675 mg, 3.4 mmol) and potassium carbonate (4.3 g, 31 mmol). To this was added in parts, picolyl chloride hydrochloride (1.23 g, 7.5 mmol). The mixture was stirred at room temperature 24 hours. The mixture was filtered free of insoluble material and the DMF solution evaporated at reduced pressure to give a solid. This was partitioned between methylene chloride (100 mL) and saturated sodium bicarbonate solution (100 ML). The organic phase was separated and washed with water (100 mL) and then brine (100 mL). The organic phase was dried over magnesium sulfate and evaporated at reduced pressure to give 0.619 g (48%) of a tan solid. MS: M+1=379.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C=O)C>O>[OH:12][C@@:11]([CH3:14])([CH2:13][N:16]([CH3:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][N:3]1[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]1[Cl:1]
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CNCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccccc1)C[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 60 °C
Reaction time: 9 h
Yield: 91.4 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (500 mg, 2.3 mmol), N-methylbenzylamine (334 mg, 2.76 mmol) and DMF (2.5 ml) was stirred at 60° C. for 9 hours. The reaction mixture was allowed to return to room temperature and added water followed by extraction with ethyl acetate twice. The organic phases were combined, washed with water three times, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford (S)-1-[2-hydroxy-3-(N-methyl-N-benzylamino)-2-methylpropyl]-2-chloro-4-nitroimidazole (712 mg, yield 91%) as a yellow oil.
Reaction SMILES: [NH:1]([C:6]([CH3:8])=[O:7])[CH2:2][C:3](O)=[O:4].[NH:9]([CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:10].[CH3:22][C:23]1[CH:24]=[CH:25][C:26](S(O)(=O)=O)=[CH:27][CH:28]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:6]([CH3:8])=[O:7])[CH2:2][C:3]([N:9]([CH2:11][C:12]([O:14][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:13])[CH3:10])=[O:4]
Reactant: CNCC(=O)OCc1ccccc1
Reactant: CC(=O)NCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCC(=O)N(C)CC(=O)OCc1ccccc1

Procedure:
Ac-Gly-OH a (4.10 g, 35.0 mmol), Sar-OBzl.PTSA b (11.71 g, 33.3 mmol), triethylamine (5.58 mL, 40.0 mmol), HOBt (1.35 g, 10 mmol) and DCC (8.25 g, 40.0 mmol) were stirred in 200 mL THF overnight. The mixture was filtered to discard DCU and removed THF in vacuum. The concentrated residue was dissolved in 100 mL ethyl acetate and washed with 100 mL 10% citric acid(aq) twice, 100 mL 5% NaHCO3(aq) twice and 100 mL brine twice, dried over MgSO4, and evaporated in vacuum to get about 9 g light yellow oily Ac-Gly-Sar-OBzl c.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1.I[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH2:21][CH3:22])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1
Reactant: CCI
Reactant: Oc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The above 5-bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzene (500 mg) was dissolved in N,N-dimethylformamide (5 ml), and thereto were added iodoethane (0.23 ml) and potassium carbonate (390 mg). The mixture was stirred at room temperature for 2 days. Added thereto was water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the desired 5-bromo-2-chloro-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)benzene (492 mg) as pale pink oil. APCI-Mass m/Z 381/383 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=O)[CH:21]=2)[NH:16][C:15]=1[C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:48]12[NH:54][CH:51]([CH2:52][CH2:53]1)[CH2:50][CH2:49]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.CO.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([CH3:28])([CH3:27])[C:24]([N:54]3[CH:48]4[CH2:53][CH2:52][CH:51]3[CH2:50][CH2:49]4)=[O:26])[CH:21]=2)[NH:16][C:15]=1[C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=1)[CH2:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CC2CCC1N2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2CCN(CCCCc2cccnc2)C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN(CCCCc2cccnc2)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of of 92.7 mg (0.15 mmol) of 2-[3-[2-[benzyloxycarbonyl-[4-(pyridin-3-yl)butyl]amino]ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid, 80.2 mg (0.6 mmol) of 7-azabicyclo[2.2.1]heptane hydrochloride, 83.2 mg (0.16 mmol) of PyBOP reagent, 0.107 mL (77.8 mg; 0.77 mmol) of triethylamine, and 0.75 mL of dry methylene chloride was stirred at room temperature in a stoppered flask for 48 hours. The solution was then partitioned between 10 mL of ethyl acetate and 10 mL of 0.5 N hydrochloric acid. The organic phase was washed with 10 mL of saturated aqueous sodium bicarbonate solution and then with 5 mL of saturated aqueous sodium chloride solution. The ethyl acetate phase was then dried (magnesium sulfate), filtered, and concentrated in vacuo at room temperature. The residue was purified by preparative TLC on 6 Analtech tapered silica gel plates (20×20 cm), which were developed in 95:5 CH2Cl2-MeOH. The product band from each plate was isolated, combined, and extracted with 95:5 CH2Cl2-MeOH. Concentration of the extracts in vacuo yielded 85.9 mg (82%) of a very pale yellow glass; virtually homogeneous by TLC in 95:5 CH2Cl2-MeOH. 506 MHz 1H NMR (CDCl3) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=697.6 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[N:13]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[S:37](Cl)(=[O:39])=[O:38]>>[CH3:12][O:11][C:9]([C:4]1[C:5]([S:28][C:25]2[CH:24]=[CH:23][C:22]([S:19]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)(=[O:21])=[O:20])=[CH:27][CH:26]=2)=[CH:6][CH:7]=[C:2]([NH:1][S:37]([C:31]2[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=2[Cl:29])(=[O:39])=[O:38])[N:3]=1)=[O:10]
Reactant: COC(=O)c1nc(N)ccc1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCOCC1
Product: COC(=O)c1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ccc1Sc1ccc(S(=O)(=O)N2CCOCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-6-methoxycarbonylpyridine and 4-(N-morpholinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichlorophenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 8.04 (1H, d, J 11 Hz, A-ring CH ortho to SO2NH), 7.62 & 7.42 (2×2 H, 2×d, 2×J 10 Hz, C-ring CH's), 7.43 (1H, s, A-ring CH ortho to 2×Cl), 7.31 (1H, d, J 11 Hz, A ring CH ortho to Cl), 7.28 & 7.18(2×1H, 2×d, 2×J 10 Hz, pyridyl CH's), 3.89 (3H, s, CH3) 3.72-3.63 (4H, m, CH2OCH2), 2.98-2.88 (4H, m, CH2NCH2). Hplc (Luna 2, Gradient 5): rt=6.00 minutes. LC/MS rt=6.69 minutes, 618/620 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]=[O:19])[CH2:14][CH2:13]1>CN(C)C=O>[N:1]1([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH:18]=[O:19])[CH2:16][CH2:17]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=CN1CCC(CCCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CN1CCC(CCCn2ccnc2)CC1
Temperature: 50 °C
Yield: 93.2 %

Procedure:
The mixture of imidazole (0.7 g, 0.01M) and NaH (50% by weight in mineral oil, 0.9 g, 0.018M) in dimethylformamide (60 ml) was heated at 50° C. for 1/2 hr. and 4-(3-bromopropyl)-1-piperidinecarboxaldehyde (2.93 g, 0.0125M) in dimethylformamide (20 ml) was added. The reaction was heated at 50° C. for 4 hrs. After the reaction, the solvent was removed in vacuo, water was added and the product was extracted with CH2Cl2 (3×50 ml). The combined extracts, dried over Na2SO4, were stripped to dryness and purified on silica gel column eluted with 10% by volume methanol--90% by volume methylenechloride to give 4[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde as an oil (2.12 g, 96%).
Reaction SMILES: [CH2:1]1[S:5](=[O:7])(=[O:6])[O:4][CH2:3][CH2:2]1.[CH3:8][C:9]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:12])=[CH2:10]>C(#N)C>[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N+:17]([CH3:19])([CH3:18])[CH2:3][CH2:2][CH2:1][S:5]([O-:4])(=[O:7])=[O:6])(=[O:12])[C:9]([CH3:10])=[CH2:8]
Reactant: O=S1(=O)CCCO1
Reactant: C=C(C)C(=O)NCCCN(C)C
Solvent: CC#N
Product: C=C(C)C(=O)NCCC[N+](C)(C)CCCS(=O)(=O)[O-]
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Into a round bottom flask is added 26.4 grams of anhydrous acetonitrile (available from Sigma-Aldrich) and 15.5 grams of propane sultone (available from Sigma-Aldrich), and this is stirred for 30 minutes. After the 30 minutes, a solution of 25.6 grams of DMAPMA in 56.5 grams of acetonitrile is added. The mixture is stirred and warmed to 35° C. A white precipitate quickly forms. Once the white precipitate takes up the bulk of the volume, the liquid is decanted. The solid is washed once with acetonitrile and again the liquid is removed by decanting. The solids are then washed in 2× volume diethyl ether. They are then filtered via funnel and washed with copious amounts (via filtration) of diethyl ether. The NMR structure is consistent with the structure of the target molecule SZ.
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][C:8]([C@@H:11]([NH:13][S@@](C(C)(C)C)=O)[CH3:12])=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]=1.Cl>CO.O1CCOCC1>[Cl:1][C:2]1[C:6]2=[N:7][C:8]([C@@H:11]([NH2:13])[CH3:12])=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]=1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc2[nH]cc(Cl)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](N)c1ccc2[nH]cc(Cl)c2n1
Temperature: 40 °C
Reaction time: 16 h
Yield: 137.4 %

Procedure:
To (R)—N—((S)-1-(3-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (1.08 g, 3.23 mmol) in anhydrous MeOH (10 mL) was added HCl (4.0 mol/L) in dioxane (14 mL). The reaction mixture was stirred at 40° C. under N2 for 16 h. Volatile solvent was removed under reduced pressure. The crude product was triturated with DCM until solid is seen. Light yellow solid was filtered and dried under a high vacuum to afford 868.2 mg (89.3%) of (5)-1-(3-chloro-1H-pyrrolo-[3,2-b]pyridin-5-yl)ethanamine as HCl salt. 1H NMR (400 MHz, DMSO) δ 11.90 (br s, 1H), 8.47 (br s, 3H), 7.93 (d, J=8.5 Hz, 1H), 7.90 (d, J=2.9 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.60 (dt, J=12.4, 6.1 Hz, 1H), 1.56 (d, J=6.8 Hz, 3H); MS (ESI) m/z: 196 [M+1]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Br:17][C:18]1C=CN=[C:20](F)[CH:19]=1.O.[CH3:26][N:27]([CH:29]=O)C>C(OCC)(=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:26]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[N:27][CH:29]=1
Reactant: Fc1cc(Br)ccn1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Temperature: 0 °C

Procedure:
Tert-butyl 4-hydroxytetrahydro-1(2H)-pyridinecarboxylate (10.0 g, 50.0 mmol) was dissolved in DMF (150 mL), and with stirring at 0° C., sodium hydride (purity 60%, 1.43 g) was added thereto. After stirred for 10 minutes, 4-bromo-2-fluoropyridine (8.75 g, 50.0 mmol) was added thereto and further stirred at room temperature for 20 hours. Water was added to the reaction solution and stirred for 10 minutes, and then the reaction solution was diluted with ethyl acetate, washed with water and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was recrystallized from ethanol-water to obtain the intended compound (11 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[OH-].[Na+]>C(O)C>[CH3:13][N:14]1[CH2:19][CH2:18][C:17]2[N:1]=[C:2]3[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]3=[CH:4][C:16]=2[CH2:15]1
Reactant: Nc1ccc([N+](=O)[O-])cc1C=O
Reactant: CN1CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCc2nc3ccc([N+](=O)[O-])cc3cc2C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of 2-amino-5-nitrobenzaldehyde (1.00 g, 6.02 mmol) and 1-methyl-4-piperidinone (0.89 ml, 7.22 mmol) in ethanol (108 ml) was added a 4N aqueous sodium hydroxide solution (9.0 ml) at room temperature, and the mixture was stirred at 60° C. for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting oil, the mixture was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the resulting residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and converted into powders with diisopropyl ether to obtain 2-methyl-8-nitro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine (430 mg).
Reaction SMILES: C(=[N:14][C@@H:15]([CH2:19][CH:20]([CH3:23])[CH2:21][CH3:22])[C:16]([OH:18])=[O:17])(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:24].O1CC[CH2:27][CH2:26]1>>[ClH:24].[CH2:26]([O:18][C:16](=[O:17])[C@@H:15]([NH2:14])[CH2:19][CH:20]([CH3:23])[CH2:21][CH3:22])[CH3:27]
Reactant: CCC(C)C[C@H](N=C(c1ccccc1)c1ccccc1)C(=O)O
Reactant: C1CCOC1
Agent: Cl
Product: CCOC(=O)[C@@H](N)CC(C)CC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A solution of (S)-2-(benzhydrylidene-amino)-4-methyl-hexanoic acid (5.09 g, 15.1 mmol) in tetrahydrofuran (100 mL) was treated with a 2N aqueous hydrochloric acid solution (50 mL) and stirred at room temperature for 1.5 hr. The mixture was concentrated in vacuo and the residue partitioned between methyl t-butyl ether and water. The layers were separated and the aqueous phase was washed with methyl t-butyl ether. The organic phases were discarded and the aqueous phase neutralized with a 1N aqueous sodium hydroxide solution (150 mL) and extracted with methyl t-butyl ether. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated in vacuo and the residue was dissolved in diethyl ether (20 mL). The diethyl ether solution was treated with 3M hydrogen chloride in diethyl ether (10 mL) and the mixture concentrated in vacuo. The residue was triturated with diethyl ether and hexanes which afforded (S)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride (2.30 g, 73%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH:21]([S:22]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])(=[O:24])=[O:23])=[CH2:20]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 100 %

Procedure:
tert-Butyl N-(2-aminoethyl)carbamate (5.00 g, 31.2 mmol) was dissolved in dry dichloromethane (50 mL). Triethylamine (7.02 g, 68.7 mmol) was added and the mixture was cooled in an ice bath, with stirring. 2-Chloroethanesulfonyl chloride (5.09 g, 31.2 mmol) was added dropwise, and the ice bath was removed. The mixture was stirred and allowed to warm to room temperature, stirring overnight. The mixture was partitioned between dichloromethane (150 mL) and 1.5M aqueous sodium carbonate solution (75 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound (7.81 g, quantitative, contains 0.4 equivalents of triethylamine) as a colourless oil. δH (d6-DMSO) 6.53 (dd, 1H, J 16.6, 9.9 Hz), 6.24 (d, 1H, J 16.6 Hz), 5.95 (d, 1H, J 9.9 Hz), 5.06 (br s, 2H), 3.31-3.27 (m, 2H), 3.16-3.12 (m, 2H), 1.45 (s, 9H). LCMS (ES+) 251 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].S(Cl)([Cl:15])=O>>[ClH:15].[Cl:15][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: O=C(NCCO)c1ccccn1
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(NCCCl)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 49 parts of N-(2-hydroxyethyl)-2-pyridinecarboxamide are added dropwise 80 parts of sulfinyl chloride while stirring vigourously. Upon completion, stirring is continued first for 3 hours at reflux and further for 2 hours at room temperature. The excess of sulfinyl chloride is evaporated and the residue is poured onto hot methanol. After cooling, the precipitated product is filtered off (the filtrate is set aside) and washed thoroughly with 2,2'-oxybispropane, yielding a first fraction of 14 parts of N-(2-chloroethyl)-2-pyridinecarboxamide hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:8]3([NH:12][CH2:11][CH2:10][NH:9]3)[C:6]=2[CH:7]=1.[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Cl>CO>[ClH:1].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17][S:13][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8]1[NH:12][CH2:11][CH2:10][N:9]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Clc1ccc2c(c1)C1(NCCN1)S2
Solvent: CO
Product: Cl
Product: Clc1ccc(CSc2ccc(Cl)cc2C2=NCCN2)c(Cl)c1

Procedure:
32 Parts of 4-chlorobenzothietane-2-spiro-2'-imidazolidine is reacted in 300 parts of methanol with 29.5 parts of 2,4-dichlorobenzyl chloride in the manner described in Example 11. The yield is 56 parts (90% of theory) and the melting point is 236° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:12]>CO>[NH2:12][C:3]([CH3:5])=[CH:2][C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])=[O:6]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: N
Solvent: CO
Product: CC(N)=CC(=O)OCCC#N
Reaction time: 8 h

Procedure:
To 10 mL of methanol was added 20 g (0.13 mole) of 2-cyanoethyl acetoacetate. The solution was cooled in ice and a slow stream of ammonia gas was passed through it for five hours. The reaction flask was stoppered and stored at 0° C. overnight. The resulting solid was collected, washed with a small amount of methanol and dried under high vacuum to give 11.1 g (0.072 mole) of 2-cyanoethyl 3-aminobut-2-enoate, 1H NMR 4.6 (s, 1H), 4.3 (t, 2H), 2.8 (t, 2H), 2.0(t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:15][CH:14]=3)=[N:9][CH:10]=[N:11][CH:12]=2)=[CH:3][CH:2]=1.Cl.[C:32](N)(=N)C>>[CH3:32][C:10]1[N:9]=[C:8]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:12][N:11]=1
Reactant: c1ccc2nc(COc3ccc(-c4ncncc4-c4ccncc4)cc3)ccc2c1
Reactant: CC(=N)N
Agent: Cl
Product: Cc1ncc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline but substituting acetamidine hydrochloride provide the title compound. 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.63 (S, 1H), 8.58(m, 2 H), 8.17 (d, J=8.7 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.81 (d, J=8.3 Hz, 1 H), 7.70 (m, 1 H), 7.60 (d, J=8.3 Hz, 1H), 7.52 (m, 1H), 7.37 (m, 2H) 7.15 (d, J=6.2, 2H), 6.93 (d, J=9.1 Hz, 2H), 5.35 (s, 2H); MS: (M+H m/z=405.2).