Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS([C:26]1[S:27][C:28]2[C:33]([N:34]=1)=[CH:32][CH:31]=[C:30]([Cl:35])[N:29]=2)(=O)=O>C(#N)C>[Cl:35][C:30]1[N:29]=[C:28]2[S:27][C:26]([O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:14][CH:15]=3)=[N:34][C:33]2=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Reactant: CS(=O)(=O)c1nc2ccc(Cl)nc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ccc(Oc2nc3ccc(Cl)nc3s2)cc1

Procedure:
21 g (0.1 mole) of ethyl 2-(4'-hydroxyphenoxy)propionate were heated under reflux for 1 hour with 16.6 g (0.12 mole) of potassium carbonate in 250 ml of acetonitrile in order to form the salt. After adding 24.9 g (0.1 mole) of 2-methylsulfonyl-5-chlorothiazolo[5,4-b]pyridine, the reaction mixture was heated under reflux for a further 10 hours. The salt constituent was filtered off while hot and the solvent was removed. The residue was distilled in a high vacuum. This gave 33.6 g (89% of theory) of ethyl 2-[4-(5-chlorothiazolo[5,4-b]pyridin-2-yloxy)-phenoxy]-propionate, of boiling point 204°-207° C./0.01 mbar, which crystallized completely after a little time (melting point 60°-62° C.). ##STR13##
Reaction SMILES: [NH2:1][C:2]1[S:17][C:5]2[CH2:6][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.[Cl:30][CH2:31][C:32]([CH2:34][Cl:35])=O.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]3[C:2]([S:17][C:5]=2[CH2:6]1)=[N:1][C:32]([CH2:34][Cl:35])=[C:31]([Cl:30])[C:18]=3[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CCl)CCl
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCN(Cc2ccccc2)C3)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(Cl)c(CCl)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 90 °C
Reaction time: 4 h
Yield: 28.6 %

Procedure:
A mixture of 2-amino-6-benzyl-3-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (10.0 g), 1,3-dichloroacetone (3.4 g), concentrated sulfuric acid (2.6 g) and acetic acid (200 ml) was stirred at 90° C. for 4 hours. After the reaction mixture was concentrated under reduced pressure, the residue was alkalinized with 2 N NaOH and then extracted with dichloromethane. The dichloromethane layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to yield 7-benzyl-3-chloro-2-chloromethyl-4-(3,4,-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno-[2,3-b:5,4-c']dipyridine (for structural formula, see below) (3.5 g, 29%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 171 to 172° C. ##STR61##
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.O=[C:12]1[CH2:18][CH:17]2[N:19](C(OC(C)(C)C)=O)[CH:14]([CH2:15][CH2:16]2)[CH2:13]1.S(=O)(=O)(O)O>O1CCOCC1>[CH3:10][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:12]1[CH2:13][CH:14]3[NH:19][CH:17]([C:18]2=1)[CH2:16][CH2:15]3
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)C1CCC(C3)N1
Temperature: 80 °C

Procedure:
4-Tolylhydrazine hydrochloride (1.90 g, 12.0 mmol) and tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.70 g, 12.0 mmol; Fluka) were heated at 50° C. in anhydrous dioxane (80 mL) for one hour. Sulfuric acid (3.2 mL) was added dropwise, and the resulting mixture was heated at 80° C. overnight. After cooling the mixture to room temperature, the dioxane phase was decanted. The remaining residue was dissolved in methanol (12 mL) and added slowly to a stirred solution of concentrated ammonium hydroxide (30 mL) kept at room temperature with a water bath. The resulting mixture was extracted with ethyl acetate (3×), and the combined organic phases were washed with brine, dried (sodium sulfate), concentrated, and purified by chromatography (silica gel, 0-5% gradient of concentrated aqueous ammonium hydroxide in acetonitrile) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.59-1.72 (m, 1H), 1.93-2.25 (m, 3H), 2.54 (d, J=16, 1H), 3.25 (dd, J=16, 4.7, 1H), 3.91-3.99 (m, 1H), 4.49 (d, J=4.8, 1H), 6.83 (d, J=8.2, 1H), 7.12 (d, J=8.2, 1H), 7.19 (s, 1H); MS (ESI) m/z 213 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH3:22])[N:15]=2)[CH:3]=1.[NH3:23]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:23])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH3:22])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCCc1cccc(Nc2cc(Cl)nnc2C(=O)OCC)n1
Product: CCCc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reaction time: 18 h
Yield: 93.5 %

Procedure:
Ethyl 6-chloro-4-(6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (340 mg, 1.06 mmol) was stirred with 7N methanolic ammonia (15.1 mL, 106 mmol). A colorless precipitate formed within a few minutes. After 18 h, the mixture was concentrated in vacuo to give 6-chloro-4-(6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (289 mg, 991 μmol, 94%) as an off-white powder. LC-MS 292.2 [M+H]+. This material was used directly without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[C:32]([F:33])=[CH:31][C:30]([Cl:34])=[CH:29][C:28]=4[F:35])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:30]1[CH:31]=[C:32]([F:33])[C:27]([NH:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:17]([O:36][CH3:37])[CH:18]=3)[N:23]=[CH:22][N:21]=2)=[C:28]([F:35])[CH:29]=1
Reactant: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1OCC1CCNCC1
Yield: 23 %

Procedure:
Using an analogous procedure to that described in Example 9, 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (95 mg, 0.2 mmol) in methylene chloride (2 ml) was treated with TFA (800 μl) to give 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (20 mg, 26%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([OH:16])[C@H:12]([NH2:15])[CH2:13][F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)Cl.[Cl:20][CH:21]([Cl:25])[C:22](Cl)=[O:23]>O>[Cl:20][CH:21]([Cl:25])[C:22]([NH:15][C@H:12]([CH2:13][F:14])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[OH:16])=[O:23]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Yield: 69.8 %

Procedure:
To a solution of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (5 g, 0.02 moles) in methylene chloride (100 ml) triethylamine (3.0 g, 0.03 mole) and dichloro acetyl chloride (3.6 g; 0.025 mole) were added at 10–15° C. After completion of reaction in 30 minutes, water (10 ml) was added and layers were separated. Solvent was distilled off from reaction mass, toluene (25 ml) and water (5 ml) were added. The product thus precipitated was filtered, washed with methylene chloride (20 ml) and crystallized from ethanol/water (4:1) to give 5 g of the title compound with purity 99.5% by HPLC.
Reaction SMILES: O[C:2]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2[C:12]3=[C:17]4[C:5]([CH2:6][CH2:7][C:8]4=[CH:9][CH:10]=[CH:11]3)=[CH:4][C:3]1=2.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:18][C:2]1[C:3]2[CH:4]=[C:5]3[C:17]4[C:8](=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]=2[CH2:14][CH2:15][CH:16]=1)[CH2:7][CH2:6]3
Reactant: CC1(O)CCCc2c1cc1c3c(cccc23)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1=CCCc2c1cc1c3c(cccc23)CC1
Yield: 92.2 %

Procedure:
A solution of 7-hydroxy-7-methyl-7,8,9,10-tetrahydroacephenanthrene (0.15 g, 0.64 mmol) and camphorsulfonic acid (0.02 g, 0.064 mmol) in toluene (20 mL) was heated at reflux for 1 h. The reaction was allowed to cool and was diluted with ethyl acetate (20 mL). The organic solution was washed with saturated aqueous sodium carbonate solution (3×15 mL) and water (3×15 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The reaction product was purified by flash chromatography to give 0.13 g (92%) of the product: MS (CI) m/e (%) 221 (M+H+, 100); 1H NMR (CDCl3, 300 MHz) δ 7.69 (d, 1H, J=8.4 Hz), 7.44 (dd, 1H, J=7.0, 8.4 Hz), 7.32 (s, 1H), 7.21 (d, 1H, J=6.9 Hz), 5.94 (m, 1H), 3.38 (s, 4H), 3.09 (t, 2H, J=8.5 Hz), 2.52 (m, 2H), 2.16 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: CCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Product: CCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)cc2C1
Yield: 12.4 %

Procedure:
In an analogous manner to procedure 1656 g, 8-amino-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (130 mg, 0.55 mmol) and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (160 mg, 0.55 mmol) were coupled to provide (1S,2S,3R,4R)-3-[5-chloro-2-(4-ethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-bicyclo-[2.2.1]hept-5-ene-2-carboxylic acid amide (34 mg, 12%) following preparative reverse-phase chromatography; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.82 (s, 1H), 7.07 (s, 1H), 6.32 (m, 1H), 6.08 (m, 1H), 4.36 (m, 1H), 4.18 (m, 1H), 3.88 (s, 3H), 3.70 (m, 2H), 3.40 (m, 2H), 3.05 (s, 1H), 2.80 (s, 1H), 2.60 (q, J=7 Hz, 2H), 1.60 (d, J=8 Hz, 1H), 1.50 (t, J=7 Hz, 3H); MS (m/e) 498 (M+1); mp 165° C. (dec.).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\C/C=C\CCCCC.C(O)(=O)CCCCCCC/C=C\CCCCCCCC>>[CH3:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4]1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCC1CCCC(=O)O1

Procedure:
A fermentation was carried out, using the procedure and materials described in Example 1, except that 10 g capsul (food grade dextrine; National Starch), 0.15 g linoleic acid, 0.15 g oleic acid and 4 g lecithin were added per liter of fermentation broth. 1.5 g/kg Delta-decalactone was obtained from the broth.
Reaction SMILES: C([NH:3][C:4]([NH:6][CH:7]1[CH2:9]C1)=[NH:5])#N.[ClH:10].N1CC[O:14][CH2:13][CH2:12]1>C(O)(C)C>[ClH:10].[N:6]1([C:4](=[NH:5])[NH2:3])[CH2:7][CH2:9][O:14][CH2:13][CH2:12]1
Reactant: N#CNC(=N)NC1CC1
Reactant: C1COCCN1
Agent: Cl
Solvent: CC(C)O
Product: N=C(N)N1CCOCC1
Temperature: 160 °C
Yield: 85 %

Procedure:
A mixture of 4.0 g (32.3 mmoles) of N-cyano-N'-cyclopropylguanidine and 3.98 g (32.3 mmoles) of morpholine hydrochloride is heated at 160° C. under a nitrogen atmosphere for 2 and a half hours. The solid mass obtained is dissolved in 200 ml of boiling isopropyl alcohol. The mixture is filtered hot and the filtrate is concentrated until a solid suspension appears. The mixture is then cooled to room temperature and 200 ml of diethyl ether are added. The reaction product crystallizes. It is filtered, washed with diethyl ether and dried. 6.8 g of N-]imino(cyclopropylamino)methyl]-4-morpholinecarboximidamide hydrochloride are obtained. Yield: 85%. M.P.: 195°-196° C.
Reaction SMILES: Cl.COC1C2CC[C@H]3[C@H](CCN3CCCC[N:21]3[C:26](=[O:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH2:23][C:22]3=[O:30])C=2C=CC=1.Cl.N1C=CC=CC=1.[OH-].[NH4+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][C:24]1([CH3:29])[CH2:25][C:26](=[O:27])[NH:21][C:22](=[O:30])[CH2:23]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCN1C(=O)CC(C)(C)CC1=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)NC(=O)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
8.8 g (22.1 mmol) of rac-cis-1-[4-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione hydrochloride were mixed well with 100 g of pyridine hydrochloride and stirred under an argon atmosphere in an oil bath for 4 hours at an oil bath temperature of 180°. After cooling the mixture was treated with ice-water, whereupon the brown solution was made alkaline with ammonium hydroxide solution and then extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulphate and evaporated. The brown oily product obtained (9.8 g) was chromatographed on a 30-fold amount of silica gel. The uniform eluates obtained in a thin-layer chromatogram using methylene chloride/ethyl acetate 1:1 were pooled and evaporated. The oil obtained crystallized after treatment with hexane. There were obtained 5.5 g (65%) of rac-cis-1-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione in the form of yellowish crystals of m.p. 131°-132°.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18](C)[C@@H:8]([C@:9]3([OH:21])[CH2:10][CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:22])[CH:4]=[CH:5]2.C(OC(=O)C)(=O)C.N>C1(C)C=CC=CC=1>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][NH:18][C@@H:8]([C@:9]3([OH:21])[CH2:10][CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:22])[CH:4]=[CH:5]2
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: N
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3)[C@H]1O5
Temperature: 97.5 °C

Procedure:
A mixture of 4,5α-Epoxy-3,14-dihydroxy-17-methyl morphinan-6-one (32.0 kg), toluene (225 L) and acetic acetic anhydride (32 L) were heated to 95-100° C. and maintained for 8.0 hrs. After reaction completion, the solvent was distilled at 60-65° C. under vacuum and acetic anhydride traces were stripped out with toluene and the residue degassed. Chlorobenzene (290 L), lithium carbonate (23.5 kg), sodium iodide (20.8 kg), DM water (3.2 L) and ethylchloroformate (280 L) were added to the degassed mass and heated to 95-105° C., the reaction was maintained at 95-105° C. for 12.0 hrs. After reaction completion, the solids were filtered and filtrate was concentrated at 70° C. under vacuum and the residue degassed. To the degassed mass acetic acid (96 L) and 15% aqueous sulphuric acid (480 L) was added and the solution was heated to 100-110° C. and maintained at 100-110° C. for 24 hrs. After reaction completion, the reaction mass was cooled to 0-5° C. and pH of the solution was adjusted to ˜4.0 with aqueous ammonia. The aqueous solution was washed with MDC and the aqueous layer was separated. The separated aqueous layer was treated with activated charcoal and filtered. The pH of the filtrate was adjusted to 9-9.5 with aqueous ammonia at below 20° C., the solution was further cooled to 0-5° C. and the product formed was filtered and dried. Yield: 20.3 kg.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.C(OC([N:23]1[CH2:28][CH2:27][O:26][C@H:25]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([CH:38]=[CH2:39])[CH:31]=2)[CH2:24]1)=O)(C)(C)C>ClCCl>[CH:38]1([C:32]2[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=2[O:36][CH3:37])[CH2:29][C@H:25]2[O:26][CH2:27][CH2:28][NH:23][CH2:24]2)[CH2:39][CH2:1]1
Reactant: CC[Zn]CC
Reactant: C=Cc1cc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)ccc1OC
Solvent: ClCCl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@@H]2CNCCO2)cc1C1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
The solution of 0.98 mL (1.1 mmol; 1.1M solution in toluene) diethyl zinc in 2 mL dichloromethane was cooled down to 0° C. Then 0.8 mL trifluoroacetic acid in 2 mL dichloromethane and after 25 min. a solution of 0.29 g diiodomethane in 2 mL dichloromethane was added. After another 20 min. 0.18 g (0.54 mmol) (R)-2-(4-methoxy-3-vinyl-benzyl)-morpholine-4-carboxylic acid tert-butyl ester dissolved in 2 mL dichloromethane was added. The ice bath was removed and after 45 min. stirring at room temperature the reaction mixture was poured on 1M hydrochloric acid and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed using MPLC and dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give the compound as a light brown oil (26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:21]1([O:27][CH2:28][CH2:29][NH:30][CH3:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:30]([CH3:31])[CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCOc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCOc1ccccc1)CC2

Procedure:
The title compound is prepared from [3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and N-(2-phenyloxyethyl)-methylamine analogously to Example 1.
Reaction SMILES: [CH3:1][C:2]1([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[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.[C@H:22]1([NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[NH2:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]1[NH:29][CH:18]1[CH2:19][CH2:20][N:15]([C:2]2([CH3:1])[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)[CH2:16][CH2:17]1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3N)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 4-methyl-4-(4-oxo-1-piperidyl)piperidine-1-carboxylate (2.96 g, 10.0 mmol) and (1S,2S)-cyclohexane-1,2-diamine (2.29 g, 20.0 mmol) in dichloromethane (80 mL) was added sodium triacetoxyborohydride (3.18, 15.0 mmol) and stirred at room temperature for 12 h. Saturated NaHCO3 (40 mL) was added, phases were separated and the aqueous layer was extracted with dichloromethane (2×60 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound, which was used for the subsequent step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH:10]=[CH:11][C:12](=O)[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:16][NH:17][CH3:18].[ClH:19]>C(OCC)(=O)C>[ClH:19].[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH:10]([N:17]([CH3:18])[CH3:16])[CH:11]=[CH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Reactant: CNC
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C1C=Cc2cc([N+](=O)[O-])ccc2CC1

Procedure:
Using the procedure of Example 1, 3-nitro-8,9-dihydro [5H] benzocycloheptene-5-one and dimethylamine were reacted to obtain a non-salified product which was treated in ethyl acetate with a solution of ethyl acetate saturated with gaseous hydrogen chloride to obtain a product which was crystallized from isopropanol to obtain 2-nitro-7-dimethylamino-6,7-dihydro [5H] benzocycloheptene hydrochloride melting at 202° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6](O)[C:7](=[CH2:15])[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH3:2].S(Br)([Br:23])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15][Br:23])[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCCOC(C)=O)C(O)C(NC=O)C(=O)OCC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C=C(CBr)CCCOC(C)=O)NC=O
Reaction time: 1 h

Procedure:
5.9 g (20.5 mmol) of 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester are dissolved in 60 ml of dichloromethane, and 1.9 ml (24.6 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 40 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, 1N KHCO3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation. 7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained in the form of a brown oil, which is reacted further in the crude state.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([N:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=4)[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([CH2:47][OH:48])=[CH:26][CH:25]=1>CS(C)=O.C(#N)C.C(=O)([O-])O.[Na+]>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH:47]=[O:48])=[C:28]2[C:32]=1[N:31]=[C:30]1[N:33]([C:37]3[C:38]([CH3:46])=[N:39][C:40]([N:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=3)[CH2:34][CH2:35][CH2:36][N:29]21
Reactant: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 0 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
Dess-Martin reagent (410 mg, 0.967 mmol) was added to a stirred solution of {9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}methanol (327 mg, 0.879 mmol) in dimethyl sulfoxide (1.0 mL) and acetonitrile (6.0 mL) at 0° C., and the mixture was stirred at 0° C. for 4 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (243 mg, 0.657 mmol, 75%).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])C.Cl.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[NH:19])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]2[N:20]=[C:4]([OH:5])[C:6]3[CH2:10][CH2:9][CH2:8][C:7]=3[N:19]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: Cl
Product: Oc1nc(-c2ccc(Cl)cc2)nc2c1CCC2

Procedure:
The title compound was prepared from 2-oxo-cyclopentanecarboxylic acid ethyl ester and 4-chloro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.01 (tt, J=7.1, 7.1 Hz, 2H), 2.69 (t, J=7.1 Hz, 2H), 2.83 (t, J=7.1 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 8.10 (d, J=8.5 Hz, 2H), 12.60 (br s, 1H); MS: m/z (ESI) 245 (M−H).