Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH:20]([NH:23][CH3:24])([CH3:22])[CH3:21]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:23]([CH:20]([CH3:22])[CH3:21])[CH3:24])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (5.0 g, 16.3 mmol) and N-isopropyl-methylamine (5.95 g, 81.4 mmol) in DMSO (50 mL) at 75° C. according to the general procedure C. Obtained as a yellow solid (4.07 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][C@H:26]([CH3:28])[C@@H:25]([OH:29])[C@H:24]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:29][C@@H:25]1[C@@H:26]([CH3:28])[CH2:27][N:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:23][C@H:24]1[NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: ClCCl
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of tert-butyl tert-butoxycarbonyl(4-((3R,4R,5S)-3-((tert-butoxycarbonyl)amino)-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)carbamate (1.0 equiv.) in DCM (0.20 M) was added TEA (1.7 equiv.), followed by MsCl (1.3 equiv.). The capped solution was stirred at rt for 90 mins. The reaction mixture was quenched with NaHCO3(sat), and extracted with EtOAc. The organic layer was washed with NaCl(sat), dried over MgSO4, filtered, concentrated to yield (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-4-yl methanesulfonate in 99% yield. LC/MS (m/z)=601.3 (MH+), Rt=0.83 min.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCO
Reactant: O=C1CCC(O)N1
Product: CCCCCCOC1CCC(=O)N1
Temperature: 60 °C

Procedure:
A mixture of 0.4 g of 5-hydroxy-pyrrolidin-2-one, 10 cm3 of n-hexanol and 0.2 g of Amberlite IR 120H is heated to 60° C. for 3 hours. The solvent is distilled off at 25° C. under 0.3 mbar. The residue is chromatographed on silica (eluent: ethyl acetate); 0.5 g of the residue is crystallized from hexane, and the expected product is obtained, m.p. 35°-37° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:14](=[O:16])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCc1ccccn1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccccn1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 2-aminomethylpyridine (0.4 mL, 4.0 mmol). Purification via using silica gel, eluting with 2:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 115 as a white solid (m.p. 130-135° C.).
Reaction SMILES: [NH4+:1].[Cl-].[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[CH2:4].[OH-].[Na+]>O>[N:8]1[CH:9]=[CH:10][C:5]([CH2:3][CH2:4][NH2:1])=[CH:6][CH:7]=1
Reactant: C=Cc1ccncc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCc1ccncc1

Procedure:
A solution of NH4Cl in 200 ml of H2O was placed in a 1L Flask. 4-Vinyl pyridine (56.4 ml, 0.52 mol) was added along with 150 ml CH3 OH and on the mixture heated at 60° for 18 h. The reaction solution was cooled to 0° in an ice bath and made basic by the addition of 30% NaOH. The basic solution was extracted with CH2Cl2 (5×100 ml) and the pooled extracts dried, then evaporated. Vacuum distillation of the residue afforded 12-1 as a colorless liquid.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.F.[OH-].[K+]>>[CH3:12][C:5]1[CH:10]=[C:9]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:8]=[C:7]([CH3:11])[CH:6]=1
Reactant: C=C(C)C
Reactant: Cc1cccc(C)c1
Agent: F
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(C)cc(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
1,3-Dimethyl-5-tertiary-butylbenzene is prepared as described in U.S. Pat. No. 2,860,169. According to this procedure, 448 g. (8.0 moles) of isobutene were dissolved in 961 g. (9.0 moles) of meta-xylene at 0° C. and added over a period of 4.2 hours to 150 g. (7.5 moles) of liquid hydrogen fluoride contained in a copper flask equipped with a stainless-steel stirrer, addition-tube and gas-outlet. The flask was cooled in an ice-bath. Stirring was continued for 2 hours after the end of the addition period. The contents of the flask were poured on crushed ice, neutralized with excess potassium hydroxide and the organic phase separated, washed with sodium bicarbonate solution, dried and distilled. The final product contained 17% by weight of unconverted meta-xylene, 76% of 1,3-dimethyl-5-tertiary-butylbenzene and 7% of higher boiling products.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH2:7][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: O=Cc1occc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Brc1ccoc1CN1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
To a solution of 3-bromofuran-2-carbaldehyde (1.5 g, 8.57 mmol) and pyrrolidine (1.42 mL, 17.14 mmol) and CH2Cl2 (30 mL) was added sodium triacetoxyborohydride (3.63 g, 17.14 mmol). The mixture was stirred at room temperature for 5 hours. The resulting mixture was diluted with EtOAc (300 mL) and the organic layer was washed with saturated NaHCO3 and brine then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (1.26 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2cc(C)ccc2o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(CBr)ccc2o1
Temperature: 25 °C

Procedure:
A mixture of the ester 25 (2.26 g, 11.1 mmol), JV-bromosuccinimide (2.37 g, 13.3 mmol) and VAZO (271 mg, 1.11 mmol) was refluxed overnight in CCl4 (50 mL) under nitrogen. The reaction mixture was cooled to the room temperature, diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography (eluent 5% EtOAc in hexane) to give ethyl 5-bromomethyl-benzofuran-2-carboxylate. This compound was dissolved in dioxane (20 ml) and a solution of NaHCO3 (1.76 g, 20.9 mmol) in water (20 ml) was added. The reaction was stirred at 80° C. during 16 h. The solvent was evaporated and the product was dissolved in EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography (eluent 20-40% EtOAc in hexane to give the title compound 26 (2.55 g, 61%) as a white solid. 1H-NMR (DMSO) δ: 7.74 (d, J=1.0 Hz, 1H), 7.71-7.70 (m, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.44 (dd, J=8.6, 1.8 Hz, 1H), 5.31 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H); 1.34 (t, J=7.0, 3H).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].O1CCOCC1.Cl.[C:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)(=[NH:30])[NH2:29]>C(=O)(O)[O-].[Na+]>[C:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[O:36])=[CH:33][CH:32]=1)(=[NH:29])[NH2:30]
Reactant: N=C(N)c1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: N=C(N)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a solution of 1-(2-naphthalenesulfonyl)piperazine hydrochloride (313 mg) in sodium bicarbonate solution (20 ml)-dioxane (20 ml) was added 4-amidinobenzoyl chloride hydrochloride (219 mg) and the solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated, to which were added dichloromethane and water. The organic layer was separated and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and the precipitate was filtered, washed with water and dried to give a colorless solid of the title compound (223 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(CCc2ccc(Cl)cc2)cc1
Product: CN(C(=O)Oc1ccc(CCc2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(4-chlorophenethyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (57%, white crystals). HPLC-MS: m/z=366.1 (M+1); Rt: 5.58 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-])=O)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH2:31][CH3:32])([CH3:30])[CH3:29])=[CH:24][C:23]=1[C:33]([CH2:36][CH3:37])([CH3:35])[CH3:34])=[O:16].C(O)(=O)C>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH2:31][CH3:32])([CH3:29])[CH3:30])=[CH:24][C:23]=1[C:33]([CH2:36][CH3:37])([CH3:35])[CH3:34])=[O:16]
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc([N+](=O)[O-])c3ccccc3c2O)c(C(C)(C)CC)c1
Solvent: CC(=O)O
Solvent: O
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1
Yield: 85 %

Procedure:
50 g of 1-hydroxy-4-nitro-N-[γ-(2,4-di-tert-amylphenoxy)propyl]-2-naphthamide obtained in Step (a) above was reduced in 500 ml of a 90% acetic acid aqueous solution using 50 g of reduced iron. The reaction mixture was poured into water and extracted with ethyl acetate. After removal of the ethyl acetate by distillation, the residue was recrystallized from ligroin to obtain 40 g of the object compound. The melting point was 132° - 133° C.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[O:15][C@H:14]([CH2:16][CH3:17])[CH2:13][NH:12][CH2:11]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:16]([C@@H:14]1[CH2:13][NH:12][CH2:11][C@H:10]([CH2:9][OH:8])[O:15]1)[CH3:17]
Reactant: CC[C@@H]1CNC[C@H](COCc2ccccc2)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H]1CNC[C@H](CO)O1
Yield: 93.9 %

Procedure:
Preparation of ER-887199: To a stirred solution of (2R,6R)-2-((benzyloxy)methyl)-6-ethylmorpholine (552.2 mg, 2.347 mmol) in MeOH (10 mL) was cycled over 10% Pd(OH)2 column with H2 gas at 1 atmosphere over 16 h using a H-Qube hydrogenation instrument. The completed reaction solution was concentrated and dried in vacuo to provide crude product, ((2R,6R)-6-ethylmorpholin-2-yl)methanol (320 mg, 2.204 mmol, 93.9% yield) that was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][O:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH2:17][O:18][CH2:19][CH3:20]
Reactant: CCOCCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccccc1Br
Temperature: 70 °C
Reaction time: 4 h

Procedure:
In DMF (120 ml) was dissolved 2-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then was added 2-bromoethylethyl ether (9.1 ml), and the mixture was stirred at 70° C. for 4 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-2-(2-ethoxyethoxy)benzene (14.8 g).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)CCC.CCOC(C)=O.C(=O)([O-])O.[Na+]>[F:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]2[CH:11]=[CH:10][NH:9][C:4]2=[N:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: Fc1cnc2[nH]ccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Fc1cnc2[nH]ccc2c1N1CCCCC1
Temperature: 180 °C
Yield: 25.9 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg) and piperidine (50 mg) in 1-butanol (0.4 mL) was heated in the microwave reactor (120° C., 0.5 hour, 180° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (10 mL) two times and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave 5-fluoro-4-(1-piperidinyl)-1H-pyrrolo[2,3-b]pyridine (10 mg) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(O)=O.C(Cl)Cl>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH3:11])[N:5]=1)[CH3:2]
Reactant: Cc1ccccc1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: O=CO
Solvent: ClCCl
Product: CC(=Nc1ccccc1C)c1cccc(C(C)=Nc2ccccc2C)n1
Reaction time: 40 h
Yield: 45.9 %

Procedure:
One g of 2,6-diacetylpyridine and 3.0 ml of o-toluidine were added to an Erlenmeyer flask with 20 ml of methylene chloride. A stirbar and 5 drops of 97% formic acid were added, and the flask was sealed and the solution was stirred for 40 hours. The solvent was then removed in vacuo, and the flask was placed in the freezer at −30° C. The resulting viscous oil was washed with cold methanol, and a yellow solid formed and was isolated by filtration and identified by 1H NMR as the desired product (959 mg, 45.9%). 1H NMR (CDCl3): δ 8.38 (d, 2, Hpyr), 7.86 (t, 1, Hpyr), 7.20 (m, 4, Haryl) 7.00 (t, 2, Haryl) 6.67 (d, 2, Haryl), 2.32 (s, 6, N═CC—CH3), 2.10 (s, 6, CH3 aryl).
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH:3]([CH3:5])[CH3:4].Cl.[CH2:15]([N:17]([CH2:20][CH2:21]Cl)[CH2:18][CH3:19])[CH3:16]>C(O)C>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:16][CH2:15][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)COc1ccccc1O
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCN(CC)CCOc1ccccc1OCC(C)C

Procedure:
The compound was prepared as described in Example 1, using sodium (2.3 g; 100 mole), o-isobutoxyphenol (8.30 g; 50 mmole) and diethylaminoethylchloride hydrochloride (8.6 g; 50 mmole) in 150 ml of ethanol. Yield 9.3 g (70%) of product, boiling at 112° C under a pressure of 0.01 mm Hg, nD25 : 1.4942.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[CH3:16][O:17][CH2:18][C:19](O)=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[C:11](=[C:19]([OH:20])[CH2:18][O:17][CH3:16])[C:10](=[O:15])[CH2:9]1
Reactant: COCC(=O)O
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COCC(O)=C1C(=O)CC(c2ccccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 65 %

Procedure:
To a solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (1.0 g), 4-dimethylaminopyridine (0.82 g) and methoxyacetic acid (0.73 g) in dimethylformamide (40 ml) was added dicyclohexylcarbodiimide (1.0 g), and the mixture was stirred at room temperature for 3 days. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. Insoluble materials were filtered off, and the organic layer was extracted with 1N sodium hydroxide solution. To the aqueous layer was added 1N hydrochloric acid to make the solution acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 5-(2-chlorophenyl)-2-(1-hydroxy-2-methoxyethylidene)cyclohexane-1,3-dione (0.86 g) as oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH2:21][C:22](O)=[O:23]>>[CH3:25][C:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:19])[CH2:21][C:22]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:23]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC(C)(CC(=O)Nn1nc(N2CCOCC2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product from Example 1B and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.16 (s, 1H), 8.30 (dd, J=7.8, 1.3 Hz, 1H), 8.01 (ddd, J=8.0, 1.4, 0.7 Hz, 1H), 7.97 (ddd, J=8.1, 6.9, 1.3 Hz, 1H), 7.89 (ddd, J=7.9, 7.0, 1.5 Hz, 1H), 7.43-7.45 (m, 2H), 7.29-7.34 (m, 2H), 7.15-7.22 (m, 1H), 3.78-3.84 (m, 4H), 3.05-3.08 (m, 4H), 2.57 (s, 2H), 1.46 (s, 6H); MS (APCI) M/Z 407 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[C:7]([CH3:23])[CH:8]=[CH:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=2)[S:5][C:4](=[S:24])[NH:3]1.[OH-].[Na+].Cl>O>[O:1]=[C:2]1[C:6](=[C:7]([CH3:23])[CH:8]=[CH:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[S:5][C:4](=[S:24])[NH:3]1
Reactant: CCOC(=O)COc1ccc(C=CC(C)=C2SC(=S)NC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C=Cc1ccc(OCC(=O)O)cc1)=C1SC(=S)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 0.12 g of Isomer A of ethyl 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate, 5 ml of water and 1 ml of 5% sodium hydroxide solution was stirred at room temperature for one hour. 10% hydrochloric acid was added to the mixture and the precipitated crystals were collected by filtration and washed with methanol to give Isomer A (54% yield) of 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:24])(=[O:23])[CH2:14][CH2:13]1)[NH:6][C:5]2=O.[NH2:26][CH:27]1[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1>>[NH:29]1[CH2:30][CH:27]([NH:26][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[N:8]=[C:7]([N:12]3[CH2:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[S:15](=[O:24])(=[O:23])[CH2:14][CH2:13]3)[N:6]=2)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)[nH]c(=O)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NC3CNC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 93-1 in Scheme 44 by using 6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one and tert-butyl 3-aminoazetidine-1-carboxylate. MS obsd. (ESI+) [(M+H)+] 410.1, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (s, 1 H), 7.87 (s, 2 H), 7.79 (s, 1 H), 7.62 (brs, 1 H), 7.45 (s, 1 H), 7.34 (d, J=8.4 Hz, 1 H), 7.22 (brs, 1 H), 5.06-4.42 (m, 5 H), 3.85 (brs, 1 H), 3.59 (m, 5 H), 2.32 (s, 3 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[F:17]>CS(C)=O.CCOC(C)=O>[F:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a warm solution of piperazine (7.78 g, 90 mmol) in DMSO (40 mL) was added dropwise 1,2-difluoro-4-nitrobenzene (2.0 mL, 18.07 mmol). The solution was stirred at 70° C. for 2 h, cooled to room temperature, diluted with EtOAc, washed with H2O, brine, dried (Na2SO4), filtered and solvent removed in vacuo to give the title compound (4.05 g, 17.98 mmol, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 3.03-3.09 (m, 4H) 3.26-3.29 (m, 4H) 6.91 (t, J=8.8 Hz, 1H) 7.91 (dd, J=13.1, 2.6 Hz, 1H) 7.96-8.01 (m, 1H). MS (ESI) m/z 226 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Cl:22][CH:23]([CH2:27][CH3:28])[C:24](Cl)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH:23]([Cl:22])[CH2:27][CH3:28])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: CCC(Cl)C(=O)Cl
Product: CCC(Cl)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 2, 7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl-hydrazine was reacted with α-chlorobutyryl chloride (CHE--CH2 --CHCl--COCl) to give 8-chloro-1-(α-chloropropyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.