Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:12][NH2:13]>>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:12][NH2:13])=[O:10]
Reactant: COC(=O)c1ccccc1N
Reactant: NN
Product: NNC(=O)c1ccccc1N

Procedure:
The intermediate o-aminobenzhydrazide is prepared by refluxing 151 g (1.0 mol) methyl anthranilate and 55 g (1.1 mol) 64% aqueous hydrazine in a 250 ml round bottom flask for 2 hours. The product is recrystallized from 1.0 liter ethyl alcohol yielding 75 g of a light yellow solid, melting at 119°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:20]3[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCCN1CCOCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCN1CCOCC1
Yield: 85.7 %

Procedure:
A solution of 6.30 g (0.024 mol) of ethyl rac-1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-napthylacetate in 100 ml of toluene was treated with 3.1 ml (0.024 mol) of 4-(2-aminoethyl)morpholine, whereupon the mixture was boiled on a water separator for 20 hours. After concentration the residue was hydrogenated with 1 g of Raney-nickel in 100 ml of ethanol at 120° and 180 bar. The product was chromatographed over silica gel with methylene chloride/methanol (9:1). There were obtained 6.80 g (86%) of oily rac-cis-1,3,3a, 4,5,9b-hexahydro-6-methoxy-3-(2-morpholinoethyl)-2H-benzo[e]indol-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1COCC1.F[C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1>CN(C=O)C>[C:43]([C:42]1[CH:45]=[CH:46][C:39]([O:1][C:2]2[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=2)[C:5]([NH:7][C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)=[O:6])=[CH:40][CH:41]=1)#[N:44]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: N#Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(C#N)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a stirred solution of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.164 mmol) in DMF (1 mL) was added a 1M solution of sodium hexamethyldisilazide in THF (0.164 mmol). The reaction was stirred at RT for 10 minutes before adding 4-fluorobenzonitrile (0.164 mmol) The reaction was stirred overnight at RT, then heated to 60° C. and stirred for a further 4 hours. The reaction was allowed to cool to RT, and treated with a further 0.2 equivalents of 4-fluorobenzonitrile and sodium hexamethyldisilazide, heated to 70° C. and stirred at this temperature for 3 hours. The reaction was cooled to RT, and treated with a further 0.2 equivalents of sodium hexamethyldisilazide, warmed to 70° C., and stirred at this temperature overnight. The solvent was removed in vacuo and the residual oil partitioned between ethyl acetate and water. The water layer was separated and re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to a residue which was chromatographed on silica, using 0-1% methanol in DCM as the eluent, to give the desired product (60% yield).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].[C:11](=[O:14])([O-])[O-].[K+].[K+].[F:17][C:18]([F:22])([F:21])[CH2:19]I>CN(C=O)C>[F:17][C:18]([F:22])([F:21])[CH2:19][O:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([O:14][CH2:11][C:18]([F:22])([F:21])[F:17])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: FC(F)(F)CI
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OCC(F)(F)F)cc(OCC(F)(F)F)c1
Temperature: 50 °C
Yield: 20.7 %

Procedure:
To a solution of 3,5-dihydroxybenzaldehyde (2.0 g, 14.5 mmol) in DMF (35 mL) was added potassium carbonate (11.0 g, 80.0 mmol) and 1,1,1-trifluoro-2-iodoethane (33.3 g, 160 mmol). The reaction mixture was heated I a sealed reactor at 50° C. for 7 days. The mixture was filtered and washed with ethyl acetate. The filtrate was added water and the organic phase isolated. The aqueous phase was extracted once more with ethyl acetated. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with toluene to give 906 mg (18%) of 3,5-bis-(2,2,2-trifluoro-ethoxy)-benzaldehyde. 1H NMR (CDCl3, 300 MHz) δ: 4.43 (q, 4H), 6.85 (t, 1H), 7.15 (d, 2H), 9.95 (s, 1H).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][N:14]=[N+]=[N-])[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[NH:14][C:4]2[CH:3]=[C:2]([F:1])[S:6][C:5]=2[CH:7]=1)=[O:17])[CH3:10]
Reactant: O=Cc1ccc(F)s1
Reactant: CCOC(=O)CN=[N+]=[N-]
Solvent: CCO
Product: CCOC(=O)c1cc2sc(F)cc2[nH]1

Procedure:
5-Fluoro-thiophene-2-carbaldehyde (see, for example, Schuetz, R. D. and Nilles, G. P., J. Org. Chem., 36: 2188-90 (1971)) was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (0.6 M of ester); acrylate organic phase washed with saturated aqueous NaCl prior to drying; acrylate not purified).
Reaction SMILES: [C:1]1([C@@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.O.C(=O)([O-])[O-].[Li+].[Li+].[Cl-].[Li+]>CN(C=O)C>[C:1]1([C@@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCc2c1c1cccc3c1n2[C@@H](c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Oc1cccc2c1c1cccc3c1n2[C@@H](c1ccccc1)CO3
Temperature: 120 °C

Procedure:
A mixture of (S)-(+)-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.397 g, 1.31 mmol), cupric chloride dihydrate (0.513 g, 3.01 mmol), and acetic acid/water (1:1, 4 mL) is heated at 120° C. for 6 h. After cooling, the mixture is partitioned between dichloromethane, water, and aq. sodium bicarbonate. The organic layers are filtered through sodium sulfate, concentrated, and stored over the weekend in the freezer. The mixture is then stirred at 130-140° C. with lithium carbonate (0.106 g, 1.44 mmol), lithium chloride (0.061 g, 1.44 mmol), and DMF (3 mL). After cooling, the mixture is partitioned between dichloromethane and sat'd aq. ammonium chloride. The organic layers are dried over sodium sulfate, concentrated, and the residue is chromatographed on silica gel gel (60 mL) using ethyl acetate/hexane (10/90) to give 0.184 g (47% for both steps) of (S)-(+)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol. [α]D=+98°(MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]1[C:16]([CH3:17])=[CH:15][S:14][C:13]1=[S:18].[CH3:19][I:20]>CC(C)=O>[I-:20].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[N+:12]1[C:16]([CH3:17])=[CH:15][S:14][C:13]=1[S:18][CH3:19]
Reactant: Cc1csc(=S)n1-c1cc(C(F)(F)F)ccc1N
Reactant: CI
Solvent: CC(C)=O
Product: CSc1scc(C)[n+]1-c1cc(C(F)(F)F)ccc1N
Product: [I-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.34 g (4.61 mmol) of 3-[2-amino-5-(trifluoromethyl)phenyl]-4-methyl-1,3-thiazole-2(3H)-thione were solubilised in acetone (25 mL), then CH3I (10 eq, 2.87 mL) was added and the solution stirred at r.t. for 12 h. 3-[2-amino-5-(trifluoromethyl)phenyl]-4-methyl-2-(methylsulfanyl)-1,3-thiazol-3-ium iodide (3a) was recovered by filtration (white powder, 1.19 g, 60%) and by evaporation of the organic layer (776 mg, 39%). Mp 194° C.; 1H NMR (300 MHz, CD3OD) δ=2.27 (3H, d, J=1.1, CH3), 2.96 (3H, s, SCH3), 7.10-7.18 (1H, m, Ar), 7.62-7.70 (2H, m, Ar), 7.86 (1H, q, J=1.1, H5); 13C NMR (75 MHz, CD3OD) δ=13.74, 18.11, 118.28, 118.36, 118.68, 119.97 (q, J=34), 125.41 (q, J=270), 126.91 (q, J=4), 130.92 (q, J=4), 149.97, 148.73, 182.40; HRMS m/z C12H12N2F3S2 [M−I]+ calcd: 305.0388, found: 305.0389.
Reaction SMILES: O[C:2]1[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]=2[N:5]=[C:6]([CH2:8][O:9][C:10](=[O:12])[CH3:11])[N:7]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]=2[N:5]=[C:6]([CH2:8][O:9][C:10](=[O:12])[CH3:11])[N:7]=1
Reactant: CC(=O)OCc1nc(O)c2c3c(sc2n1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)OCc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 85 %

Procedure:
The acetic acid 4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (4 g, 0.014 mol) in 20 ml of POCl3 was refluxed for 2 h. The excess of POCl3 was distilled off; the reaction mixture was quenched with ice, and extracted with ethyl acetate (3×25 ml). The combined organic layers were washed with bicarbonate solution, dried over anhydrous sodium sulphate, concentrated and dried to give acetic acid 4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (3.5 g, 85%) as brown solid. 1H NMR (400 MHz, CDCl3): δ 1.85-1.95 (m, 4H), 2.20 (s, 3H), 2.84-2.90 (m, 2H), 3.04-3.10 (m, 2H), 5.30 (s, 2H); LC-MS: [M+H]=297.2 & 299.1 m/z.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]1([N:13]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH:21]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:19][CH2:18]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO.[H][H]>[Pd].C(O)(=O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:34]1([N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[CH2:21][CH2:22]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1cccc(OC2=CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(OC2CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1
Yield: 65.6 %

Procedure:
A mixture of 7.7 g. (0.014 moles) of 3,6-dihydro-N,N-diphenyl-4-[3-(trifluoromethyl)phenoxy]-1(2H)-pyridinepropanamine ethanedioate (1:1) (preparation described in Example 16), 90 ml. of methanol, 10 ml. of acetic acid and 0.5 g. of 20% Pd/c is shaken under 50 psi. of hydrogen at room temperature for about 4 hours. The reaction mixture is then filtered, and the solvent is evaporated. The residue is initially recrystallized from aqueous isopropanol, then recrystallized from aqueous isopropanol, and again recrystallized from aqueous ethanol to give 5.0 g of N,N-diphenyl-4-[3-(trifluoromethyl)phenoxy]-1-piperidinepropanamine ethanedioate (1:1), mp. 189°-190.5° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][N:16]=3)[CH:6]=[CH:5][C:4]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:19]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:22][CH2:21]4)[O:17][N:16]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3noc(C4CCNCC4)n3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3noc(C4CCN(CCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 95 mg (0.25 mmol) of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]piperidine hydrochloride and 55 μl (0.38 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[O:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl.[K].CC(C)([O-])C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1=[O:19]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)OCCCCCl
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCCCOC1=O

Procedure:
Prepared analogously to Example 39b from 4-chloro-butyl 2-methyl-4-nitro-phenyl-carbamate with potassium-tert.-butoxide in DMF.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:7]=[C:6]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1)(=[O:3])[CH3:2].[Se](=O)=[O:23].C.[O:26]1CCO[CH2:28][CH2:27]1>O>[CH2:15]([O:14][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH:2]([O:26][CH2:27][CH3:28])[OH:23])[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1COCCO1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)oc12
Reactant: O=[Se]=O
Solvent: O
Product: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)oc12

Procedure:
20 g (71 mmol) 7-acetyl-5-benzyloxy-3H-benzoxazol-2-one and 8 g (72 mmol) selenium dioxide are refluxed for 8 hours in the presence of activated charcoal in 100 mL dioxane and 3.1 mL water. The solid is filtered off, the solvent is distilled off and the residue is combined with 50 mL ethanol. The mixture is refluxed for 15 minutes and then filtered through activated charcoal. The solid precipitated on cooling is suction filtered after 3 hours and washed with ethanol and diethyl ether.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[CH3:22][CH:23]([CH3:26])[CH:24]=O.[BH3-]C#N.[Na+]>CO.CCOC(C)=O>[CH3:1][N:2]([CH2:22][CH:23]([CH3:26])[CH3:24])[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CN(C)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (100 mg, 0.33 mmol, 1.00 equiv) in methanol (5 ml) was added 2-methylpropanal (50 mg, 0.69 mmol, 2.00 equiv) at room temperature and the reaction solution was stirred for 1 h. Then NaBH3CN (45 mg, 0.72 mmol, 2.00 equiv) was added and stirred overnight at ambient temperature. The resulting solution was diluted with EtOAc (100 mL), washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 54.0% in 13 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give 75 mg (63%) of the desired 1-N-methyl-1-N-(2-methylpropyl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine as a white solid. MS: (ES, m/z): 359 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 4.07-4.09 (m, 1H), 3.02 (t, 2H), 2.99 (t, 2H), 2.54-2.59 (m, 3H), 2.37-2.39 (m, 5H), 2.18-2.21 (m, 2H), 1.95-1.99 (m, 2H), 1.81-1.85 (m, 1H), 1.45-1.61 (m, 4H), 1.01 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[C:28]([O-:31])(=[O:30])[CH3:29].[Na+].C(OCC)(=O)C>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:28]([O:31][CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4])(=[O:30])[CH3:29]
Reactant: CC(=O)[O-]
Reactant: COc1ccccc1CN(C(=O)CCl)c1ccccc1Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccccc1CN(C(=O)COC(C)=O)c1ccccc1Oc1ccccc1
Yield: 96 %

Procedure:
In 10 ml of benzene were stirred 1.01 g of N-chloroacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline, 1.30 g of sodium acetate and 170 mg of tetra-n-butyl ammonium bromide at 80° C. for 5 hours. The reaction mixture was poured into ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:3) to give 1.03 g of N-acetoxyacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: C([NH:4][C:5]1[C:23]([Cl:24])=[CH:22][C:8]([C:9]([NH:11][CH:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:13]2)=[O:10])=[C:7]([O:25][CH3:26])[CH:6]=1)(=O)C.[OH-].[K+].CCOCC>C(O)C.O>[NH2:4][C:5]1[C:23]([Cl:24])=[CH:22][C:8]([C:9]([NH:11][CH:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:13]2)=[O:10])=[C:7]([O:25][CH3:26])[CH:6]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC1CCN2CCCCC2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN2CCCCC2C1
Yield: 75 %

Procedure:
Hydrolysis of 4-acetylamino-5-chloro-2-methoxy-N-(2-quinolizidinyl)-benzamide (600 mg) with potassium hydroxide (500 mg) in ethanol (10 ml) and water (2 ml) at reflux for 4 hours followed by isolation through ether afforded one of the isomers of 4-amino-5-chloro-2-methoxy-N-(2-quinolizidinyl)-benzamide (400 mg), m.p. 175°-8°.
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH2:6]([NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[NH:19])=[NH:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:30][C:31]([CH3:33])=[O:32]>>[C:31]([OH:2])(=[O:32])[CH3:33].[CH3:30][C:31]1([CH3:33])[N:16]=[C:15]([NH:14][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:19]1
Reactant: CCCCCCCCCNC(=N)NC(=N)NCCc1ccccc1
Reactant: CC(C)=O
Reactant: CO
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCCNC1=NC(C)(C)N=C(NCCc2ccccc2)N1

Procedure:
350 ml of methanol, 350 ml of acetone and 1.9 ml of concentrated hydrochloric acid were added to 31.0 g (76.7 mmol) of N1-phenethyl-N5-nonyl-biguanide dihydrochloride. The mixture was refluxed for 16 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in 350 ml of ethanol, and to the solution were added 250 ml of water and 31 ml of 5N sodium hydroxide. The mixture was refluxed for 1.5 hours, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ether to obtain 16.3 g of colorless crystals having a melting point of 72 to 76° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[CH:8]=1.Cl>O>[O:14]=[C:11]1[C:10]2[CH:15]=[CH:16][C:7]([CH2:6][CH:2]=[O:1])=[CH:8][C:9]=2[CH2:13][O:12]1
Reactant: O=C1OCc2cc(CC3OCCO3)ccc21
Agent: Cl
Solvent: O
Product: O=CCc1ccc2c(c1)COC2=O
Temperature: 40 °C

Procedure:
5-(1,3-Dioxolan-2-ylmethyl)-2-benzofuran-1(3H)-one (61 g, 280 mmol) was combined with water (2.2 L) in a 5 L round bottomed flask equipped with a Claisen adapter, thermocouple, stir bar and nitrogen bubbler. Aqueous HCl solution (2M, 1.14 L, 2.29 mol) was added and the resulting mixture was heated at 40° C. for 8 h. Then the mixture was stirred overnight at room temperature. The mixture was extracted three times with 2 L of ethyl acetate. The combined organic layers were concentrated to give (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. MS: in/z 177 (M+1)+.
Reaction SMILES: [Li+].[BH4-].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][C:8]=1C1C=CC(I)=CC=1>>[NH:5]1[CH:6]=[CH:7][CH:8]=[CH:4]1.[CH:8]1[CH:7]=[C:6]([CH2:3][C:4]2[NH:5][CH:6]=[CH:7][CH:8]=2)[NH:5][CH:4]=1
Reactant: Cc1[nH]ccc1-c1ccc(I)cc1
Agent: [BH4-]
Agent: [Li+]
Product: c1c[nH]c(Cc2ccc[nH]2)c1
Product: c1cc[nH]c1

Procedure:
The synthesis of the β-substituted EH begins in the same manner as the prior synthesis of β-substituted dipyrromethanes (Balasubramanian, T.; Lindsey, J. S. Tetrahedron 1999, 55, 6771-6784) but employs a number of significant improvements (FIG. 54). The iodophenyl substituted pyrrole (3) is readily prepared from 4-iodobenzaldehyde, monoethyl malonate, and tosylmethylisocyanide. The ethoxycarbonyl group was removed by treatment with NaOH in ethylene glycol at 160° C. to give the 3-(4-iodophenyl)pyrrole (4) in 91% yield as pale brown crystals. It is noteworthy that this single-step decarboxylation is superior to the two-step transformation on similar pyrrole compounds (Pavri, N. R.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649-2651). Vilsmeier-Haack formylation of 4 yielded a mixture of two regioisomers (˜6:1 ratio) which were readily distinguished by 1H NMR spectroscopy (See Experimental Section). The major isomer was the desired compound (5) and was obtained in pure form by recrystallization in 62% yield. Protection of the pyrrolic nitrogen with the BOC group (Tietze, L. F.; Kettschau, G.; Heitmann, K. Synthesis 1996, 851-857) gave pyrrole 6 in quantitative yield. Reduction to alcohol 7 was achieved by treatment with LiBH4 at low temperature (longer reaction time or higher temperature led to the over-reduced and deprotected compound 2-methyl-3-(4-iodophenyl)pyrrole). Treatment of 7 with excess pyrrole under acidic conditions furnished the β-substituted, mono-protected dipyrromethane 8 in 68% yield. Excess pyrrole is necessary to minimize the formation of the tripyrromethane, while protection of the pyrrolic nitrogen is necessary to facilitate the reaction, avoid self condensation and allow the subsequent selective monoacylation. This methodology afforded the β-substituted dipyrromethane as a single regioisomer, in contrast to earlier methodology which gave a mixture of two regioisomers (Balasubramanian, T.; Lindsey, J. S. Tetrahedron 1999, 55, 6771-6784).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH2:7][CH2:6]2.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][Cl:19]>C(Cl)CCl>[Cl-:19].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N+:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1
Reactant: COc1cc2c(cc1OC)CCN=C2
Reactant: Fc1ccccc1CCl
Solvent: ClCCCl
Product: COc1cc2c(cc1OC)CC[N+](Cc1ccccc1F)=C2
Product: [Cl-]

Procedure:
The title compound is prepared analogously to Example A from 6,7-dimethoxy-3,4-dihydroisoquinoline and 2-fluorobenzyl chloride in ethylene chloride. Melting point: 196°-198° C. (Decomp.)