Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19]([C:21]1[CH:29]=[CH:28][C:24]2=[N:25][O:26][N:27]=[C:23]2[CH:22]=1)=[O:20]>C1COCC1>[N:25]1[O:26][N:27]=[C:23]2[CH:22]=[C:21]([C:19](=[O:20])[C:7]#[C:6][C:4]([CH3:8])([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])[CH3:5])[CH:29]=[CH:28][C:24]=12
Reactant: CON(C)C(=O)c1ccc2nonc2c1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccc2nonc2c1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a −78° C. stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (0.49 g, 2.367 mmol) in dry THF (20 mL), n-BuLi (3.70 mL, 5.917 mmol, 1.6 M hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of N-methoxy-N-methylbenzo[c][1,2,5]oxadiazole-5-carboxamide (0.557 g, 3.550 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at −78° c. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc hexanes to afford 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.45 g, 63%) as a colorless oil.
Reaction SMILES: O1CCCC1.B.[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=O)[NH:13][C:12]=2[CH:19]=1.BrC1C=C2C(CCCC2=O)=CC=1.CO>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:19]=1
Reactant: O=C1CCCc2ccc(Br)cc2N1
Agent: B
Agent: O=C1CCCc2ccc(Br)cc21
Solvent: CO
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)NCCCC2
Yield: 92 %

Procedure:
Borane tetrahydrofuran complex (1 M solution in tetrahydrofuran, 21 mL, 21 mmol) was added to a solution of 8-bromo-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (prepared from 7-bromo-3,4-dihydro-2H-naphthalen-1-one in analogy with the general procedure described in J Chem. Soc. (C) 1969, 183; 1.00 g, 4.17 mmol) in tetrahydrofuran, and the solution was heated at reflux for 2 h. After cooling, methanol (21 mL) was added, and volatile material was removed by distillation. The residue was taken up in 5% ethanolic sulfuric acid solution (12 mL) and heated at reflux for 2 h, then basified to pH 10 by addition of 2 M aq. sodium hydroxide solution and partitioned between water and ethyl acetate. The organic layer was dried (MgSO4) and evaporated. Chromatography (SiO2, heptane-ethyl acetate 2:1) yielded 8-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine (865 mg, 92%). White solid, MS (ISP) m/e=226.1 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]1[CH2:17][CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.[CH3:30]I>CC(C)=O>[CH3:30][N:11]1[CH2:10][CH2:9][C:8]2[C:2](=[O:1])[N:3]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=3)[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[O:6][C:7]=2[CH2:12]1
Reactant: CI
Reactant: COC(=O)c1ccc(OCCN2C(=O)c3ccncc3Oc3ccccc32)cc1
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCN2C(=O)C3=C(CN(C)CC3)Oc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
Title compound 448 (0.249 g, 0.638 mmol) was solubilized in acetone (15.0 mL) and the methyl iodide (2.0 mL) was added. The reaction mixture was stirred in a sealed tube at 60° C. for 18 hours. The mixture was cooled down and evaporated. The residue was dissolved in methanol (15 mL) and Pt black (55 mg) was added. The reaction mixture was stirred over 55PSI of hydrogen for 3 hours. The catalyst was filtered and the filtrate was evaporated. The crude was purified by flash chromatography (75-100% ethyl acetate in hexanes with 1.5% of ammonium hydroxide) to afford title compound 452 (133 mg, 51%). 1H NMR (DMSO-d6) δ (ppm): 7.89 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 7.07 (dd, J=7.4, 1.2 Hz, 1H), 6.88 (d, J=8.2 Hz, 2H), 4.38 (t, J=4.9 Hz, 2H), 4.31 (t, J=4.9 Hz, 2H), 3.84 (s, 3H), 3.17 (s, 2H), 2.52-2.51 (m, 2H), 2.44 (m, 2H), 2.36 (s, 3H). MS (m/z): 409.4 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([F:24])[C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[C:34]([CH2:36][C:37](O)=[O:38])#[N:35].CCN=C=NCCCN(C)C>C(Cl)Cl>[C:34]([CH2:36][C:37]([NH:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([F:24])[C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[O:16])[CH2:13][CH2:14]1)=[O:38])#[N:35]
Reactant: CN1CCN(C(=O)C2CCN(c3c(N)cncc3F)CC2)CC1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)CC#N)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of [1-(3-amino-5-fluoro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanone hydrochloride 17b (300 mg, 0.8383 mmol) and DIPEA (541.8 mg, 730.2 μL, 4.192 mmol) in DCM (8 mL) was added cyanoacetic acid 7 (106.9 mg, 1.257 mmol). The reaction mixture was cooled on an ice bath and EDCI (241.0 mg, 1.257 mmol) was then added. The mixture was stirred at room temperature overnight, then heated under reflux for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL), washed with water (2×10 ml), then saturated sodium hydrogen carbonate solution (10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford the desired product 8a as an orange foam (292 mg, 90%). MS (ES+) 389.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].[CH3:18][S:19][CH3:20].ClN1C(=O)CCC1=O.C(N(CC)CC)C>[Cl-].[Na+].O.C(Cl)Cl>[NH2:1][C:2]1[C:3]([CH2:18][S:19][CH3:20])=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCOC(=O)c1ccc(OC)c(N)c1
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)c1ccc(OC)c(N)c1CSC
Temperature: -30 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
Pentyl 3-amino-4-methoxybenzoate (0.744 g, 4.45 mmol), methylene chloride (15 ml) and dimethylsulfide (0.33 ml, 4.50 mmol) were mixed, and after cooling to -30° C., N-chlorosuccinimide (601 mg, 4.5 mmol) was added to this solution. After sti ring for 1 hour, triethylamine (0.627 ml, 4.5 mmol) was added, and the mixture was refluxed under heating for 0.5 hour. Saturated brine (0.5 ml) was added to stop the reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hemne/ethyl acetate=4/1) to give pentyl 3-amino-4-methoxy-2-methylthiomethylbenzoate (0.83 g, 82%) as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:5][C:4](=[O:14])[CH:3]=1.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[S:25]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:17])[CH3:16].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:5][C:4](=[O:14])[C:3]=1[S:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[CH:15]([CH3:17])[CH3:16]
Reactant: O=C1C=C(O)CC(c2ccccc2)N1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)ccc2C(C)C)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C)C)c(SC2=C(O)CC(c3ccccc3)NC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method III using 95.6 mg of 5,6-dihydro-4-hydroxy-6-phenyl-2(1H)-pyridinone, 180 mg of toluene-4-thiosulfonic acid S-(2-isopropyl-5-methylphenyl) ester (prepared as per Ranasinghe and Fuchs, Synthetic Communications 18: 227 (1988)) and 0.08 ml of triethylamine in 5 ml of absolute ethanol. The solution was stirred overnight at room temperature. Purification by flash chromatography using CH2Cl2 /isopropanol (99/1 to 95/5) as eluent gave a solid (m.p. 184°-186° C). 1H NMR (CDCl3) δ 1.28 (d, 3 H), 1.29 (d, 3 H), 2.23 (s, 3 H), 2.98 (d, 2 H), 3.52 (qn, 1 H), 4.85 (t, 1 H), 5.63 (s, 1 H), 6.78 (s, 1 H), 6.96 (m, 1 H), 7.14 (d, 1 H), 7.35-7.44 (m, 5 H), 7.55 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8](=[O:15])[N:9]2[OH:14])=[CH:4][CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.P([O-])([O-])([O-])=O>[CH2:17]([O:14][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[C:11]=2[C:12]#[N:13])[NH:6][C:7](=[O:16])[C:8]1=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1c(Cl)ccc2[nH]c(=O)c(=O)n(O)c12
Reactant: BrCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: N#Cc1c(Cl)ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c12
Reaction time: 20 h
Yield: 98.1 %

Procedure:
To a solution of 2,0 g (~8,4 mmol) 7-chloro-8-cyano-1-hydroxyquinoxaline-2,3(1H,4H)-dione in a mixture of 150 ml ethanol and 175 ml 0,1M phosphate buffer pH 7.4 was added 3.0 g (~17,4 mmol) of benzylbromide. Stirring was continued for 20 h at 24° C. The precipitate was filtered off to give the title compound (2.7 g; 98%), m.p. 227°-229° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: CCCS(=O)(=O)Nc1cccc(CO)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To propane-1-sulfonic acid (2-fluoro-3-hydroxymethyl-phenyl)-amide (66, 0.20 g, 0.81 mmol) in tetrahydrofuran (5.0 mL) was added Dess-Martin periodinane (0.377 g, 0.89 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (67, 100 mg, 50.0%). MS (ESI) [M−H+]+=244.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([F:18])=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:19]#[C:20]Br>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:3]([O:10][C:11]1[N:16]=[C:15]([NH:17][C:20]#[N:19])[C:14]([F:18])=[CH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Nc1nc(OCc2ccccc2)ncc1F
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CNc1nc(OCc2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a mixture of sodium hydride (0.65 g, 0.27 mol) in dry THF (10 mL), was added 2-benzyloxy-5-fluoro-pyrimidin-4-yl amine (2.0 g, 0.009 mol) dissolved in THF (15 mL) at room temperature under nitrogen. The mixture was allowed to stir at room temperature for 30 min and then cyanogen bromide (1.45 g, 0.0136 mol) in THF (10 ml) was added to the reaction mixture and allowed stir at room temperature for 16 h. The reaction was diluted with sat. sodium bicarbonate (2×5 mL) and extracted with EtOAc (3×40 mL). The organic phase was dried over Na2SO4, and concentrated to a give a crude solid which was recrystallized by adding minimum quantity of ethyl acetate and hexane until solution became turbid. The solvent was decanted and a gummy brown solid was obtained. The gummy brown solid was rinsed with Et2O (2×10 mL) and allowed to stand in Et2O while stirring for 1 h, until a free solid formed. The resulting solid was filtered and dried to give the title compound (1.7 g, 77%) as a pale brown solid: mp 150-152 dec.; 1H NMR (300 MHz, DMSO-d6) δ 7.80 (bs, 1H), 7.43 (m, 5H), 5.20 (s, 2H); MS (EI) m/z 245 (M)+.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][N:7]=[CH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:12]([O:14][CH3:15])=[O:13]>C(OCC)(=O)C.[Fe]>[NH2:19][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[CH:8]=[N:7][O:6][CH3:5]
Reactant: CON=Cc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CON=Cc1cc(C(=O)OC)ccc1N

Procedure:
In a 5-liter three-necked round-bottomed flask was placed 0.9 l of 5% aqueous acetic acid and 157 g (2.8 moles) of iron. To the resulting well-stirred mixture was added 166.6 g (0.7 moles) of the previously prepared methyl 3-methoxyiminomethyl-4-nitrobenzoate dissolved in 0.9 l of ethyl acetate followed by dropwise addition of 0.9 l of acetic acid while keeping the temperature below 35° C. The resulting mixture was stirred at 35° C. for 30 minutes and filtered through diatomaceous earth. The filtrate was poured into 5 l of water. The aqueous phase was separated and washed with ethyl ether (2×500 mL). The combined organic layers were washed sequentially with water (4×500 mL), saturated aqueous sodium bicarbonate (2×500 mL), water (2×500 mL), and brine (1×400 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator yielding 130 g of the expected methyl 4-amino-3-methoxyiminomethylbenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: CCCC(=O)Nc1ccc2c(c1)CCCN2
Product: CCCC(=O)Nc1ccc2c(c1)CCCN2C1CC(C)N(C(=O)c2ccc(OC)c(OC)c2)c2ccccc21
Yield: 36 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (800 mg, 2.44 mmol) prepared in Reference Example 1 and N-(1,2,3,4-tetrahydro-6-quinolinyl)butanamide (1.33 g, 6.1 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (463 mg, yield: 36%) as a colorless oil. (cis:trans=1:1.3)
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1.S(=O)(=O)(O)O.[CH2:26](O)[CH3:27]>>[CH2:26]([O:10][C:9]([C:7]1[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]([CH2:2][F:1])([CH2:19][F:20])[CH:8]=1)=[O:11])[CH3:27]
Reactant: O=C(O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
A mixture of 41.7 g of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carboxylic acid, 20 ml of sulfuric acid and 300 ml of ethyl alcohol was heated to reflux for 6 hours. The reaction mixture was poured into ice water and the precipitated crystals were filtered off to give 42.7 g of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carboxylic acid ethyl ester; m.p. 96-98° C.;
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:30]=[CH:29][C:13]3[N:14]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=5)[N:17]=[C:15]4[S:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[H][H]>[Ni].C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:30]=[CH:29][C:13]3[N:14]4[CH:19]=[C:18]([C:20]5[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=5)[N:17]=[C:15]4[S:16][C:12]=3[CH:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1

Procedure:
7-(2-Morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b]benzothiazole was dissolved into methanol and THF and placed in a hydrogenator. Raney nickel was added and the vessel was pressurized with hydrogen and stirred for >24 hours. The reaction mixture was concentrated to a thick paste and diluted with methyl tert-butyl ether. The resulting solids were filtered and washed with methyl tert-butyl ether and dried under vacuum to give 7-(2-morpholin-4-yl-ethoxy)-2-(4-aminophenyl) imidazo[2,1-b]benzothiazole.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:38])[CH2:16][CH2:17][CH:18]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[N:20]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:19]3=[O:37])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:41]1[N:46]2[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]2)[CH2:42]1>C1(C)C=CC=CC=1>[Br-:1].[F:36][C:33]1[CH:32]=[CH:31][C:30]([N:20]2[C:19](=[O:37])[CH:18]([CH2:17][CH2:16][CH:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N+:43]56[CH2:48][CH2:47][N:46]([CH2:45][CH2:44]5)[CH2:41][CH2:42]6)=[CH:40][CH:39]=4)=[CH:10][CH:11]=3)[OH:38])[CH:21]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(OCc4ccc(CBr)cc4)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: COc1ccc(C2C(CCC(O)c3ccc(OCc4ccc(C[N+]56CCN(CC5)CC6)cc4)cc3)C(=O)N2c2ccc(F)cc2)cc1
Product: [Br-]

Procedure:
Compound (29) and DABCO were dissolved in toluene and reacted analogously to Example IV, giving the product (30) as a colorless solid of molecular weight 716.70 (C39H43BrFN3O4); MS (ESI): 636.3 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([O:21]CC)=O)[CH2:14][CH2:13]1.[NH2:24][NH2:25]>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([NH:24][NH2:25])=[O:21])[CH2:14][CH2:13]1
Reactant: CCOC(=O)CN1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc3ccccc3c2)CC1

Procedure:
Synthesized according to General Procedure C: 6{25} (5.74 g, 18.4 mmol, 1 equiv.), anhydrous hydrazine (1.7 mL, 55.2 mmol, 3 equiv.), ethanol (37.2 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{25} (4.49 g, 82%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.17 (br s, 1H), 7.82-7.78 (m, 3H), 7.71 (s, 1H), 7.47-7.42 (m, 3H), 3.86 (br s, 2H), 3.64 (s, 2H), 3.06 (s, 2H), 2.53 (br s, 8H). 13C-NMR (125 MHz, CDCl3): δ 170.4, 135.4, 133.1, 132.6, 127.8, 127.5, 127.5, 127.2, 125.9, 125.5, 62.9, 60.5, 53.5, 53.0.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc2c(cc1[N+](=O)[O-])C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
50 g (250 mmoles) of 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene are dissolved in 200 ml of acetic anhydride. The solution is cooled to 0° C. and there is slowly added a solution of 10.5 ml (250 mmoles) of nitric acid, 20 ml of acetic acid and 20 ml of acetic anhydride, while maintaining the temperature between 0° and 5° C. The reaction mixture is then stirred for 1 hour at ambient temperature, poured into ice water and filtered. The resulting solid is washed with water. The solid is dissolved in methylene chloride, washed with water and then with a saturated solution of sodium bicarbonate, dried on MgSO4 and evaporated. 45.8 g (74%) of 2-methyl-3-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 143°-144° C. are obtained.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:13][CH2:14][CH3:15].[Na+]>C(O)C>[CH2:14]([O:13][C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:15]
Reactant: Cc1cc2nnc(N)n2nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2cc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
6-Chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.005; 1 g) was dissolved in ethanol (50 ml), admixed under argon with sodium ethoxide (2.2 g) and stirred at 60° C. for 1 h. Then the mixture was dried and the residue was purified using a 40 g silica gel cartridge (0-20% dichloromethane-ethanol gradient in 40 min). The clean product fractions were combined and dried. 480 mg of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]([CH:11]=[C:12](I)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[F:17][C:18]([F:26])([F:25])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:24]4[N:20]([CH2:19][C:18]([F:26])([F:25])[F:17])[N:21]=[CH:22][N:23]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: FC(F)(F)Cn1cncn1
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Product: FC(F)(F)Cn1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Yield: 10 %

Procedure:
Following the procedure for 184, 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine and 1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole were reacted to give 9-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.109 g, 10%). 1H NMR (400 MHz, DMSO) δ 8.28 (t, J=21.9, 1H), 8.11 (t, J=7.9, 2H), 7.51-7.35 (m, 1H), 7.32 (d, J=2.0, 1H), 5.88 (q, J=8.8, 2H), 4.76-4.29 (m, 4H). MS (ESI(+)): m/z 413.9 (M+H).