Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([C:39]2([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40]2)[CH:35]=[CH:36][C:37]=1[Cl:38].[OH-].[Na+].[C:49](=[O:52])(O)[O-].[Na+].[CH3:54][O:55][C:56]1[CH:64]=[CH:63][C:59]([C:60](Cl)=[O:61])=[C:58](OC)[C:57]=1[O:67][CH3:68]>ClCCl.C(OCC)(=O)C.CC(C)=O>[CH3:68][O:67][C:57]1[CH:58]=[C:59]([CH:63]=[C:64]([O:52][CH3:49])[C:56]=1[O:55][CH3:54])[C:60]([N:41]1[CH2:42][CH2:43][C:39]([C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)([CH2:44][CH2:45][OH:46])[CH2:40]1)=[O:61]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: O=C([O-])O
Reactant: COc1ccc(C(=O)Cl)c(OC)c1OC
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine (+)-3-(3,4-dichloro-phenyl)-3-(2-hydroxyethyl)-pyrrolidine (R, R)-di-p-anisoyltartaric acid salt (772.7 g, 1140 mmol) and acetone (5 L). Cool in to 0°-10° C. and add aqueous sodium hydroxide solution (46 g, 1105 mmol, in 5 L of water). Add sodium bicarbonate (479 g, 5700 mmol). While maintaining the temperature at 0°-10° C., add dropwise over 30 minutes, trimethoxy-benzoyl chloride (262.9 g, 1140 mmol). After 3 hours, add ethyl acetate (5 L) and allow to warm to ambient temperature. Separate the layers and extract the aqueous layer 3 times with ethyl acetate. Combine the organic layers and extract 1M sodium hydroxide solution, 1M hydrochloric acid solution, and then saturated aqueous sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Treat the residue with dichloromethane and evaporate in vacuo the title compound: Rf =0.36 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [C:1]1([N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N(C2C=CC=CC=2)/[C:28](/[C:36]2[CH:41]=[CH:40]C=CC=2)=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=CC=CC=1>>[C:15]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:40][C:41]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]=[CH:28][CH:36]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: C(=C(\c1ccccc1)N(c1ccccc1)c1ccccc1)\c1ccccc1
Product: C(=C(c1ccccc1)N(c1ccccc1)c1ccccc1)c1cccc2ccccc12

Procedure:
This compound was synthesized from diphenylbenzylamine and N-phenyl-1-naphthaldimine under the same conditions outlined for (E)-1-(diphenylamino)-1-phenyl-2-phenylethylene above. Recrystallization from ethyl acetate/methanol gave small crystals mp 170°-2° C. 1H NMR (200 MHz, CDCl3) δ (assignment): 6.60-6.90 (m, 2H, aromatic), 6.80-7.38 (m, 15H, aromatic), 7.52-7.85 (m, 6H, aromatic). MS [m/e (70 eV, % of base peak)] C10H7CHCPhNPh2 397 (M+., 43.1), 180 (PhCNPh+, 100), 77 (Ph+, 43.2); HRMS (m/z) for C30H23N (M+.), calcd. 397.183 found 397.195.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:26](=[N:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:27])C>O>[CH3:27][C:26]1[N:28]=[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:10])[N:9]=1
Reactant: CCOC(C)=NC(=O)c1ccccc1
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(-c2ccccc2)n(-c2ccccc2C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
Next, into a 300-mL recovery flask were put 8.68 g of o-tolylhydrazine hydrochloride, 100 mL of carbon tetrachloride, and 35 mL of triethylamine (Et3N), and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 8.72 g of N-(1-ethoxyethylidene)benzamide obtained in Step 1 above was added to this mixture, and the mixture was stirred at room temperature for 24 hours. After a predetermined time elapsed, water was added to the reaction mixture, and the aqueous layer was subjected to extraction with chloroform. The organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate added thereto. The obtained mixture was gravity-filtered, and the filtrate was concentrated to give an oily substance. The obtained oily substance was purified by silica gel column chromatography. Dichloromethane was used as a developing solvent. The obtained fraction was concentrated to give 3-methyl-1-(2-methylphenyl)-5-phenyl-1H-1,2,4-triazole (abbreviation: HMptzl-mp) (an orange oily substance, 84% yield). A synthesis scheme of Step 2 is shown in (a-2) below
Reaction SMILES: [O:1]1[CH:8]2[CH:2]1[CH:3]1[CH2:9][C:7]2([CH2:10][CH3:11])[CH:6]2[CH:4]1O2.[S-:12]C#N.[NH4+]>O1CCCC1>[S:12]1[CH:6]2[CH:4]1[CH:3]1[CH2:9][C:7]2([CH2:10][CH3:11])[CH:8]2[CH:2]1[O:1]2
Reactant: CCC12CC(C3OC31)C1OC12
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC12CC(C3OC31)C1SC12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
6-Epoxyethyl-3-oxatricyclo [3.2.1.0 2.4 ] octane (42g, 0.28mol), ammonium thiocyanate (23g, 0.30 mol) and tetrahydrofuran (125 ml) were placed in a 200-ml egg-plant type flask, and stirred with a magnetic stirrer in a water bath of 50° C. Although first the reaction solution was completely uniform, a white precipitate was deposited about 30 minutes later. 5 hours later, the reaction mixture was suction filtered by a Nutsche to remove the white precipitate, and the filtrate was concentrated by a rotary evaporator. Toluene (250 ml) and water (80 ml) were added to the concentrate, and after separation of the water layer the toluene layer was washed (80 ml ×2). The toluene layer was dried over magnesium sulfate and the toluene was then distilled away by a rotary evaporator. The concentrate was simply distillated under reduced pressure to obtain 6-epithioethyl-3-oxatricyclo [3.2.1,02.4 ] octane (40g, yield 87%). Colorless oil; b.p. 90-93° C./2mmHg; nD 1.5294; IR (neat) 3030(m), 2968(s), 1446(m), 1375(m), 1319(m), 1035(m), 1007(m), 849(s) cm-1 ; 13C NMR(CDCl3) δ23.1, 23.3, 24.1, 24.3, 24.5, 25.3, 26.5, 26.9, 29.7, 30.2, 31.9, 32.3 (CH2); 35.6, 36.2, 36.5, 36.7, 36.9, 37.4, 38.2, 39.0, 41.1, 41.2, 42.1, 42.3, 44.1, 45.3, 47.2, 47.7, 48.5, 48.6, 50.2, 50.4, 50.6, 50.7, 51.0(CH).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]([S:18][CH3:19])=[C:9]2[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]=12)=[NH:5])C.[CH3:20][NH:21][NH2:22].[CH2:23](O)C>>[CH3:16][C:12]1([CH3:17])[CH2:11][C:10]2=[C:6]([C:4]3[N:5]=[CH:20][N:21]([CH3:23])[N:22]=3)[S:7][C:8]([S:18][CH3:19])=[C:9]2[C:14](=[O:15])[CH2:13]1
Reactant: CNN
Reactant: CCOC(=N)c1sc(SC)c2c1CC(C)(C)CC2=O
Reactant: CCO
Product: CSc1sc(-c2ncn(C)n2)c2c1C(=O)CC(C)(C)C2
Temperature: 50 °C
Yield: 15 %

Procedure:
6,6-Dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboximidic acid ethyl ester (1.0 g, 3.37 mmol) was dissolved in ethanol (60 mL) and methyl hydrazine (0.16 g, 3.37 mmol) was added. The solution was heated at 50° C. for 7 h then evaporated to dryness and the residue was taken up in formic acid (20 mL). The solution was heated at 100° C. for 16 h then evaporated to dryness. The residue was dissolved in CH2Cl2 and washed with saturated potassium carbonate solution, then evaporated to dryness. The crude product was purified by chromatographed on silica gel, eluting with ethyl acetate to yield the title compound as a yellow solid (0.15 g, 15%). mp 146-148° C. Found: C, 54.55; H, 5.46; N, 13.27%. C14H17N3OS2 requires; C,54.70; H, 5.77; N, 13.27%. 1HNMR (250 MHz, CDCl3) δ 1.05 (6H, s), 2.44 (2H, s), 2.63 (3H, s), 2.74 (2H, s), 3.96 (3H, s), 7.98 (1H, s). MS (ES+) 308 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=[O:24])[C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=2)[CH:7]=1.[H-].[Na+].[CH3:27]I>CN(C)C=O>[CH3:27][N:4]1[CH:5]=[C:6]([C:8](=[O:24])[C:9]2[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=2)[CH:7]=[C:3]1[S:2][CH3:1]
Reactant: CSc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2-Methylthio-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (1 g) was added to a cooled, stirred suspension of 0.28 g of sodium hydride (50% in mineral oil) in 20 ml of anhydrous dimethylformamide under nitrogen. After 45 minutes at room temperature, the mixture was cooled to 0° C. and 0.25 ml of methyl iodide was added. After 30 minutes, the reaction mixture was poured into a 10% HCl-ice-water mixture, then extracted three times with 100 ml ethyl acetate. The organic layer was washed five times with 100 ml water, dried and evaporated to dryness. Crystallization of the residue from ethyl acetate-hexane gave 0.93 g of the title compound (mp 173°-175° C.).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)[C:6]2[NH:10][C:9](=O)[NH:8][C:7]=2[CH:12]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:9]1[NH:8][C:7]2[CH:12]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=[C:5]([C:13]3[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=3)[C:6]=2[N:10]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F

Procedure:
The benzoimidazol-2-one from step (a) above (1.1 g, 3.3 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 350 (M+1).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH2:8]1[O:18][C:17]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=2[O:9]1.N1CCCCC1.CC(O)=O>C(O)(C)C>[CH2:8]1[O:18][C:17]2[CH:16]=[CH:15][C:12]([CH:13]=[C:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[CH:11][C:10]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc2c(c1)OCO2)C(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.1 %

Procedure:
A mixture of pentane-2,4-dione (20.0 g, 200 mmol), 3,4-methylenedioxybenzaldehyde (32.2 g, 200 mmol), piperidine (1.98 mL, 20.0 mmol), and HOAc (1.20 mL, 20.0 mmol) in 200 mL of isopropanol were stirred at room temperature for 3 days (no precipitate). The solvent was remove in vacuo, and the crude product was heated to 50-70° C. under reduced pressure for 0.5 hours (no solids). The crude product was chromatographed on 900 g of silica packed with 10% EtOAc-hexane. The column was eluted with increasing amounts of EtOAc (10% to 30%, 2.5%/2 L change) to give 19.1 g (41%) of the desired product as a yellow solid: mp 79-80° C. The product was used in the next step after spectral characterization.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.O.C(O)(=O)C.[Br:17]Br>>[Br:17][C:5]1[S:1][C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:3]=2[CH:4]=1
Reactant: BrBr
Reactant: O=C1CCCCc2sccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCCc2sc(Br)cc21
Temperature: -5 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-one (4.96 g, 29.8 mmol) in water (23.0 mL, 1200 mmol) and acetic acid (23.0 mL, 4000 mmol) at −5° C. was added a solution of bromine (1.6 mL, 31 mmol) in acetic acid (3.2 mL, 56 mmol) dropwise and the reaction mixture was stirred at −5° C. for 1 hr. The reaction mixture was quenched into aqueous sodium acetate, ethyl acetate (30 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated and dried under high vacuum to afford 7.3 g product as a brownish solid (99.0% yield). LCMS: (FA) ES+ , 246. 1H NMR (300 MHz, CDCl3) δ: 7.35-7.36 (br s, 1H), 2.98-3.0 (m, 2H), 2.68-2.73 (m, 2H), 1.85-2.0 (m, 4H).
Reaction SMILES: [Cl-].[NH4+].C(O)C.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N+:21]([O-])=O)[CH:12]=1>[Fe].O>[NH2:21][C:13]1[CH:12]=[C:11]([C:7]2[O:6][CH:10]=[CH:9][CH:8]=2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(-c2ccco2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2ccco2)cc1N
Temperature: 25 °C
Yield: 63.4 %

Procedure:
Water (0.56 mL), ammonium chloride (18 mg), and iron powder (94 mg) were added to an ethanol (2.1 mL) suspension of methyl 4-(furan-2-yl)-2-nitrobenzoate (0.14 g), followed by heating to reflux for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then ammonium chloride (18 mg), iron powder (31 mg), and water (0.28 mL) were added thereto, followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the obtained residue, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-95% hexane/ethyl acetate] to obtain 78 mg of methyl 2-amino-4-(furan-2-yl)benzoate as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[C:17]#[N:18]>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([C:17]#[N:18])[CH:19]=[CH:20][C:21]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[O:12][CH:11]=[CH:10][C:5]1=2
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2ccc(C#N)cc2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-chloro-4-fluorobenzonitrile instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8].CCOCC>CCO>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: NN
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)C(=O)OC)cc2)CC1
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)C(=O)NN)cc2)CC1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Hydrazine monohydrate (0.15 mL, 3.34 mmol) was added in one portion to a stirred solution of ethyl trans-4-(4-{[methoxy(oxo)acetyl]amino}phenoxy)cyclohexanecarboxylate (150 mg, 3.04 mmol) in EtOH (3 mL) and the reaction mixture was stirred for 20 minutes. Ether (10 mL) was added and the mixture was cooled to 5° C. The mixture was filtered to give the title compound (Intermediate 80) (129 mg, 85%) as a solid that was used without further purification; MS m/e MH+ 350.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=3)C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:34][CH2:35][CH2:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]([CH:46]2[CH2:48][CH2:47]2)[C:38]1=[O:49].[I-].[Na+].[C:52](=[O:55])([O-])[O-:53].[K+].[K+]>CC(=O)CC>[CH:46]1([N:39]2[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[N:37]([CH2:36][CH2:35][CH2:34][N:15]3[CH2:16][CH2:17][C:12]4([N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH2:9][N:10]([CH2:19][C:20]5[CH:21]=[CH:22][CH:30]=[CH:31][C:32]=5[C:52]([O:53][C:12]([CH3:17])([CH3:13])[CH3:11])=[O:55])[C:11]4=[O:18])[CH2:13][CH2:14]3)[C:38]2=[O:49])[CH2:48][CH2:47]1
Reactant: O=c1n(CCCCl)c2ccccc2n1C1CC1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCNCC3)C2=O)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(CCCn3c(=O)n(C4CC4)c4ccccc43)CC2)C1=O
Temperature: 81 °C
Reaction time: 16 h
Yield: 197.4 %

Procedure:
A mixture of tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (163.5 mg, 0.372 mmol, 1 equiv), 1-(3-chloropropyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (93 mg, 0.372 mmol, 1 equiv), sodium iodide (22.3 mg, 0.15 mmol, 0.4 equiv) and potassium carbonate (102.8 mg, 0.74 mmol, 2 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using preparative thin layer chromatography to afford the title compound as a cream powder (240 mg, 65%); MS for C38H44FN5O4 m/z 654.34 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[C:3]1=[O:23].[CH3:24][C:25]([CH3:27])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][N:18]([CH:25]([CH3:27])[CH3:24])[CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[C:3]1=[O:23]
Reactant: CN1CCN(c2ccc(-n3cc4c(n3)CCNCC4)cc2)C1=O
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCc2cn(-c3ccc(N4CCN(C)C4=O)cc3)nc2CC1
Temperature: 25 °C

Procedure:
A solution of 1-methyl-3-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-imidazolidinone (may be prepared as described in Description 29) (44.0 mg, 0.14 mmol) in dichloromethane (3 ml) was treated with acetone (41 μl, 0.56 mmol) and acetic acid (1 drop) and stirred at room temperature. Sodium triacetoxyborohydride (60.0 mg, 0.28 mmol) was added and the mixture stirred for 3 hours and then overnight with a further portion of acetone and sodium triacetoxyborohydride added. The mixture was diluted with methanol and passed down a SCX cartridge eluting with methanol and then a 2M solution of ammonia in methanol. The basic fractions were combined and evaporated to afford the title compound (E10); MS (ES+) m/e 354 [M+H]+.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]([CH:21]=1)=[N:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)[CH:17]=1)[CH:12]=2.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[ClH:2].[ClH:1].[ClH:2].[CH2:28]([N:30]([CH2:31][CH3:32])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]([CH:21]=1)=[N:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][N:19]([CH2:20][CH3:11])[CH2:18][CH3:17])[CH:17]=1)[CH:12]=2)[CH3:29]
Reactant: CCNCC
Reactant: ClCCCCOc1ccc2cc3ccc(OCCCCCl)cc3nc2c1
Agent: Cl
Product: CCN(CC)CCCCOc1ccc2cc3ccc(OCCCCN(CC)CC)cc3nc2c1

Procedure:
A mixture of 2.0 g. of 3,6-bis(4-chlorobutoxy) acridine hydrochloride and 150 ml. of diethylamine is heated in a steel bomb at 100° C. for 24 hours. The excess diethylamine is removed under reduced pressure. The residue is dissolved in 150 ml. of chloroform and this chloroform solution is washed with two 30 ml. portions of saturated aqueous sodium bicarbonate, then dried over sodium sulfate and filtered. The chlorofrom is evaporated and the residue is dissolved in 50 ml. of absolute ethanol. A 10 ml. portion of 6 N hydrochloric acid in isopropanol is added giving the desired product as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)(=[O:15])[CH2:11][C:12]([CH3:14])=O.[NH2:38]/[C:39](/[CH3:45])=[CH:40]\[C:41]([O:43][CH3:44])=[O:42]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]([CH3:45])[NH:38][C:12]([CH3:14])=[C:11]2[C:10]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:21][CH2:20]2)=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc(Cl)c1
Yield: 28.3 %

Procedure:
A mixture of m-chlorobenzaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-(4-benzhydryl-1-piperazinyl)ethyl methyl 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 74°-80° C. (sintering). Yield 28.3%. IR(Nujol)cm-1 : 3325, 1695, 1680. NMR(CDCl3) δ: 2.32(6H,s, ##STR36## 3.60(3H,s,COOCH3), 4.96(1H,s,C(4) --H), 5.64(1H,broad s, NH).
Reaction SMILES: [C:1]1([C:7](=[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.CCO.[OH-].[Na+]>Cl.CCOC(C)=O>[C:1]1([C:7](=[C:21]2[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26]2)[C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)C1
Temperature: 25 °C

Procedure:
A mixture of 17 THF (35 mL) and absolute EtOH (35 mL) was charged with 1 N aqueous NaOH (46 mL) and heated to reflux. After 90 min the reaction was cooled to room temperature. The reaction was diluted with 1 N aqueous HCl (55 mL) and EtOAc (100 mL). The organic fraction iwa washed with water (2×75 mL) and brine (1000 mL) then dried (MgSO4) and concentrated to a white solid. This solid was triturated with hexane (25 mL) and recrystallized from CH3CN (100 mL) to yield: 1.87 g (84%) of the title compound 18 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.35 (s, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.15-7.31 (m, 7H), 6.45 (d, J=15.9 Hz, 1H), 1.91 (s, 2H), 1.89 (s, 2H), 1.26 (s, 2H), 0.88 (s, 6H), 0.87 (s, 6H). LCMS (ESI): m/z 373 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29](O)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH:25]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]([NH:13][C@@H:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C@H:9]([CH2:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:30])[CH2:10]2)=[O:15])=[N:17]1)([CH3:27])[CH3:26]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: C1COCCN1
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)N3CCOCC3)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from ((2S,4S)-1-(tert-butoxycarbonyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)acetic acid (step 1 of Example 13) and morpholine.