Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].Br.[Br:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([O:27][CH3:28])=[CH:22][C:20]=1[NH2:21].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Br:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([O:27][CH3:28])=[CH:22][C:20]=1[NH:21][C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: COc1cc(N)c(Br)cc1Cl
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3c2C=C2N=CN=C2C3)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
A mixture of 0.12 g (0.52 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.2 g (0.63 mmol) of 2-bromo-4-chloro-5-methoxyaniline hydrobromide and 0.06 g (0.52 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at reflux temperature for 1 hour, cooled to room temperature, poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried. The solid is purified by silica gel chromatography utilizing a gradient of methylene chloride/methanol (97:3 to 90:10) to yield 0.1 g of 8-(2-bromo-4-chloro-5-methoxy-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as a yellow solid, mp 257° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.BrBr>C(O)(=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(C2=NNC(=O)CC2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1nccn1-c1ccc(-c2ccc(=O)[nH]n2)cc1

Procedure:
Similarly, reaction of 4,5-dihydro-6-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone with bromine in acetic acid as described in this Example gives 6-[4-(2-methyl-1H-imidazol-1-yl)phenyl)-3(2H)-pyridazinone (13b).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:23]2=[CH:24][CH:25]=[N:26][CH:27]=[C:22]2[C:5]2[C:6]([OH:21])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:29].[N:30]1([CH2:36][CH2:37][CH2:38][C:39](O)=[O:40])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:29].[CH3:28][C:2]1([CH3:1])[C:23]2=[CH:24][CH:25]=[N:26][CH:27]=[C:22]2[C:5]2[C:6]([O:21][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CC(CCCc1ccccc1)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CC(CCCc1ccccc1)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-[5-phenyl-2-pentyl]-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-[5-phenyl-2-pentyl]-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:14]([O:16]C)=O)[CH:11]=[CH:12][CH:13]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:18]>CO>[C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:14]([NH2:18])=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1cccc2oc(C(C)(C)C)nc12
Solvent: CO
Product: CC(C)(C)c1nc2c(C(N)=O)cccc2o1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Methyl 2-t-butyl-4-benzoxazole carboxylate (0.1 g; 0.46mmol) was dissolved in methanol (5 ml), and to this was added aqueous ammonia (5 ml). The mixture was warmed to 40° C. and left to stir for 6 hours at ambient temperature. Once the reaction was complete the solvent was removed under reduced pressure and the product was recrystallised from boiling ethyl acetate and petrol (73%).
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]1[CH2:12][N:11]([CH2:13][CH2:14][N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][C:16]2=[O:26])[CH2:10][C@@H:9]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:8]1)(C)C.[ClH:38].O1CCOCC1>C(Cl)Cl.CO>[ClH:38].[NH2:28][CH2:27][C@H:9]1[CH2:8][C@@H:7]([OH:6])[CH2:12][N:11]([CH2:13][CH2:14][N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][C:16]2=[O:26])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(CCn2c(=O)ccc3ccc(F)cc32)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC[C@H]1C[C@@H](O)CN(CCn2c(=O)ccc3ccc(F)cc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To cis-1,I-dimethylethyl ({(3RS,5RS)-5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-[2-(7-fluoro-2-oxo-1(2H)-quinolinyl)ethyl]-3-piperidinyl}methyl)carbamate (410 mg; 0.78 mmol) in DCM (9 ml) and MeOH (1 ml) was added 4N HCl in 1,4-dioxane (1 ml; 4.0 mmol) and the reaction was allowed to stir at room temperature under nitrogen for 2 hours. The reaction was concentrated under reduced pressure to give the desired compound (270 mg; 100%) as a yellow solid which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:26])[CH3:25])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([OH:26])[CH3:25])=[CH:21][CH:22]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: CC(O)Cc1ccc(N)cc1
Product: CC(O)Cc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and 1-(4-aminophenyl)-2-propanol (step 1 of Example 6).
Reaction SMILES: [Br:1]Br.[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>CO.CCOCC>[Br:1][CH2:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrBr
Reactant: CC(=O)CCCCCCCc1ccccc1
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: O=C(CBr)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine (5.21 g, 0.033 mol) was added to a solution of 9-phenylnonan-2-one (7.12 g, 0.033 mol) in dry methanol (75 ml) and stirred for 2 hours at room temperature. Water (50 ml) was added and stirring continued for 18 hours at room temperature. Ether (175 ml) and water (100 ml) were added, the organic layer washed with dil. NaHCO3, water (×2), dried (MgSO4) and evaporated under reduced pressure to an oil (5.39 g). Petroleum ether (40° C.-60° C., 50 ml) was added and the mixture cooled to -10° C. and filtered. The solid obtained was re-dissolved in ether (40 ml) and evaporated under reduced pressure to an oil (4.06 g) which was was further purified by flash chromatography on silica gel using hexane/ethyl acetate to give 1-bromo-9-phenylnonan-2-one a pale yellow solid (3.80 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]([CH2:7][N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:31][NH:32][CH2:33][CH2:34][OH:35])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.[Cl:47][CH2:48][C:49](Cl)=[O:50].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CO>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:46][CH:45]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:31][N:32]([CH2:33][CH2:34][OH:35])[C:49](=[O:50])[CH2:48][Cl:47])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:42][CH:41]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CNCCO)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN(CCO)C(=O)CCl)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A mixture of 2-(((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinyl)methyl)amino)ethanol (Example 225, Step 1; 0.118 g, 0.189 mmol), chloroacetyl chloride (0.023 mL, 0.284 mmol) and triethylamine (0.040 mL, 0.284 mmol) in THF (1 mL) was stirred at ambient temperature for 2 h. 2 M K2CO3 (0.2 mL, aq.) and MeOH (1 mL) were added. After 1 h, water was added to the mixture and it was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give N-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinyl)methyl)-2-chloro-N-(2-hydroxyethyl)acetamide (0.110 g, 0.157 mmol, 83% yield). m/z (ESI, +ve ion) 699.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:20])[N:15]=[CH:16]N(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[S:20][C:22]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=NC(=S)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)C(=O)CBr
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)C(C)(C)C)s2)CC1
Yield: 87 %

Procedure:
Prepared in analogy to example 82 (b) from 4-(dimethylaminomethylene-thiocarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 82(a)) and 1-bromo-pinacolone. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 87%). MS (m/e): 354.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[C:3]=1[C:19]([O:21]C)=O.[NH3:23]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[C:3]=1[C:19]([NH2:23])=[O:21]
Reactant: N
Reactant: CCCOc1ccccc1-c1cc(C)c(C(=O)OC)c(=O)[nH]1
Product: CCCOc1ccccc1-c1cc(C)c(C(N)=O)c(=O)[nH]1

Procedure:
Methyl 1,2-dihydro-4-methyl-2-oxo-6-(2-propoxyphenyl)-pyridine-3-carboxylate (0.53 g) and saturated methanolic ammonia (25 ml) was heated in a sealed vessel at 70°-85° C. for 34 hours. The residue after evaporation was triturated with methanol (10 ml) to give a solid, 0.28 g, m.p. 239°-242° C. Recrystallisation from ethanol afforded the title compound, 0.18 g , m.p. 244°-246° C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([CH3:1])[S:13][C:12]=2[CH:16]=1
Reactant: COc1ccc2ccsc2c1
Reactant: [Li]CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2cc(C)sc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-butyllithium in hexanes (20 ml, 50 mmole) was added under argon to a solution of 6-methoxybenzo[b]thiophene 1a (3.68 g, 22.4 mmole) in THF (150 ml) at −75°. After stirring at −75° for a further 30 minutes, the cooling bath was exchanged and the reaction warmed to −10° C. prior to addition of CH3l (4.2 ml, 9.58 g, 67 mmole). The resultant mixture was stirred at 0° C. for an additional 30 minutes, then allowed to gradually warm to room temperature before diluting with saturated NaHCO3 (150 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 4.2 g of an amber oil which was purified by silica gel chromatography. Elution with hexane: Et2O (98:2) and evaporation of the appropriate fractions gave 3.63 g (91%) of a colourless oil. 1H NMR (DMSO-d6) δ7.57 (1H, d, J=8.7 Hz), 7.43 (1H, d, J=2.4 Hz), 6.99 (1H, s), 6.92 (1H, dd, J=2.4, 8.7 Hz), 3.78 (3H, s), 2.50 (3H, s). Anal. Calcd. for C10H10OS: C, 67.38; H, 5.66; S, 17.99. Found: C, 67.42; H, 5.74; S, 17.87.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:44][OH:45].C(Cl)(Cl)Cl>CO>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([CH2:44][OH:45])[C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Camptothecin (100 mg, 0.287 m-mol) was suspended in methanol (25 ml) and then dissolved therein by addition under ice-cooling of 75% sulfuric acid (10 ml). To the solution was added dropwise under reflux with stirring an aqueous solution (100 ml) of ammonium persulfate (15 g, 0.0657 mol) over 16 hours. The reaction mixture was poured into ice water (100 ml) and the organic matter was extracted with a mixture (1:1, 500 ml) of dioxane-chloroform and then thrice with chloroform (100 ml×3). The organic phases were combined, dried with anhydrous magnesium sulfate, filtered and then evaporated until dryness under reduced pressure. The remaining solid having an orange color was warmed (50°-60° C.) with methanol (200 ml) and stirred for 30 minutes. An insoluble matter was collected by filtration, dried under reduced pressure and recrystallized from dimethylformamide-dioxane whereupon 40 mg (36.9%) of 7-hydroxymethylcamptothecin were obtained as light yellow white prismatic crystals having a melting point of 274°- 276° C. (dec.). Rf value 0.125 (5% methanol-chloroform).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Cl-:15].[Al+3].[Cl-:17].[Cl-].ClCl>C(Cl)Cl>[Cl:15][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([Cl:17])[C:2]=1[CH3:1])[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1
Reactant: [Cl-]
Agent: ClCl
Agent: [Al+3]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)CCC(=O)O)cc1Cl
Yield: 44.2 %

Procedure:
To a mixture of 3-(4-methylbenzoyl)propionic acid (7.5 g) and methylene chloride (250 ml) was added slowly portionwise aluminum chloride (15 g) at 0° C. After the addition was completed chlorine gas was bubbled in slowly at 0° C. After 6 hours the reaction mixture was poured into a mixture of hydrochloric acid and ice and extracted with methylene chloride (3×150 ml), the combined organic layers were washed with water, dried and evaporated under vacuum yielding 3-(3,5-dichloro-4-methylbenzoyl)propionic acid as a yellow solid (4.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]4[CH3:28])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:29]=1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.CC1NC2C=CC=CC=2N=1.[CH3:65][C:66]([OH:70])([C:68]#[CH:69])[CH3:67]>>[OH:70][C:66]([CH3:67])([CH3:65])[C:68]#[C:69][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]4[CH3:28])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:29]=1
Reactant: Cc1nc2ccccc2n1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cc1nc2ccccc2[nH]1
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Product: Cc1nc2ccccc2n1Cc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Yield: 24 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with 2-methylbenzimidazole) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (26 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 89 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 89%). 1H NMR (300 MHz, CDCl3): δ 2.45 (s, 3H), 3.45-3.60 (m, 4H), 3.76-3.88 (m, 4H), 4.09 (s, 3H), 6.85 (d, J=6.2 Hz, 2H), 7.03-7.68 (m, 4H), 8.16 (d, J=6.0 Hz, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.Cl.[NH2:26][OH:27].C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:26][OH:27])=[NH:18])=[CH:19][CH:20]=1
Reactant: NO
Reactant: CCCCN(CCc1ccc(C#N)cc1)c1nc2ccccc2o1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCN(CCc1ccc(C(=N)NO)cc1)c1nc2ccccc2o1
Temperature: 65 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
290 mg 4-[2-(Benzooxazol-2-yl-butyl-amino)-ethyl]-benzonitrile were dissolved in a mixture of 10 ml tetrahydrofuran and 20 ml methanol. 930 mg hydroxylamine hydrochloride were added followed by the addition of 2.24 ml triethylamine. The reaction mixture was stirred at 65° C. for two hours. The cooled reaction mixture was diluted by the addition of 100 ml ethyl acetate, then washed three times with 40 ml water. The organic layer was dried over MgSO4, then the solvent was removed in vacuo to obtain 280 mg 4-[2-(Benzooxazol-2-yl-butyl-amino)-ethyl]-N-hydroxy-benzamidine as a pale yellow oil.
Reaction SMILES: C(O[C:4]1([C:15]([F:18])([F:17])[F:16])[CH:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5]1)C.[O:19]1[CH2:24][CH2:23][NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]1=2>FC(F)(F)C(O)C(F)(F)F>[CH2:7]([CH:6]1[C:4]([C:15]([F:16])([F:17])[F:18])([OH:5])[C:25]2[C:21]3=[C:20]([O:19][CH2:24][CH2:23][N:22]13)[CH:28]=[CH:27][CH:26]=2)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc2c(c1)NCCO2
Reactant: CCOC1(C(F)(F)F)OC1CCc1ccccc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: OC1(C(F)(F)F)c2cccc3c2N(CCO3)C1CCc1ccccc1

Procedure:
A solution of 2-ethoxy-3-phenethyl-2-(trifluoromethyl)oxirane (340 mg, 1.3 mmol) and 3,4-dihydro-2H-benzo[b][1,4]oxazine (177 mg, 1.3 mmol) in hexafluoroisopropanol was stirred at room temperature overnight. The solvent was evaporated and the residue purified by reverse-phase HPLC (CH3CN/0.1% trifluoroacetic acid) to yield 5-phenethyl-6-(trifluoromethyl)-2,3,5,6-tetrahydro-[1,4]oxazino[2,3,4-hi]indol-6-ol as a solid (MS m/z 350 MH+).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.Cl>[Fe].O>[NH2:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:18]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
50.0 g (0.158 mol) of methyl 2-(N-tert-butylsulfamoyl)-4-nitrobenzoate (prepared according to DE-OS 4 236 902) are added to a mixture of 180 ml of acetic acid and 75 ml of water, and the mixture is heated to 80° C. 26.5 g (0.474 mol) of iron powder are added a little at a time in such a manner that the temperature does not rise above 85° C. The mixture is subsequently stirred at 80° C. for 4 h, 85 ml of 2N HCl are added at this temperature and the mixture is allowed to cool to 25° C. The mixture is filtered off and the solid is washed thoroughly with water. The solid is subsequently 3× extracted hot with in each case 250 ml of ethyl acetate. The ethyl acetate phase is evaporated, and the residue is triturated with diisopropyl ether and dried. This gives 37.7 g (83% of theory) of methyl 4-amino-2-(N-tert-butylsulfamoyl)benzoate of m.p. 198-1990° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(Cl)Cl.CO>[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Solvent: ClCCl
Solvent: CO
Product: Cc1c(Cc2ccncc2)nnc(Nc2cccc(Cl)c2)c1C
Temperature: 30 °C

Procedure:
The compound is prepared starting from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.153 g meta-chloroaniline in the manner described in Example 82A. After heating for 20 h to 1 30° C., siginificant quantities of 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine are still present (TLC). For this reason, a further 0.153 g meta-chloroaniline is added and heated for another 24 h to 1 30° C. Processing is in the manner described for Example 82A. Title compound is obtained after FC in CH2Cl2/methanol 19/1: m.p. 164-167°. 1H-NMR (250 MHz, CDCl3): δ=8.45 (s, wide, 2H); 7.70 (t, 1H); 7.45 (dd, 1H); 7.25-7.10 (m, 3H)); 7.00 (dd, 1H); 6.20 (s, wide, 1H); 4.25 (s, 2H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 325, 327 (M+H for 35Cl and 37Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:13]1=[O:27].CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:17]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:13](=[O:27])[C@@H:12]2[CH3:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: C[C@@H]1NCCN(CCCN2CCCCC2)C1=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H]1C(=O)N(CCCN2CCCCC2)CCN1C(=O)Nc1cccc(Cl)c1
Yield: 82.4 %

Procedure:
3-Chlorophenyl isocyanate (36 mg, 0.23 mmol) was added to a solution of (S)-3-methyl-1-(3-piperidin-1-yl-propyl)-piperazin-2-one (intermediate 20; 52 mg, 0.21 mmol) and 4-methylmorpholine (21 mg, 0.21 mmol) in N,N-dimethylformamide (1 ml), then after 16 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (68 mg, 84%). Colorless gum, MS (ISP)=393.2 (M+H)+.