Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:18](O)C>[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6](/[C:9](=[CH:14]\[CH:13]=[CH2:18])/[CH:10]=[N:11]/[CH2:12][NH2:15])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reactant: CCO
Agent: [Pd]
Product: C=C/C=C(/C=N/CN)N1CCN(CC)CC1
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 1-ethyl-4-(6-nitropyridin-3-yl)piperazine (500 mg, 2.12 mmol) in ethanol (20 mL) was added 10% Pd/C (113 mg, 0.11 mmol) and the resulting mixture was stirred under a hydrogen atmosphere for 18 h. The reaction mixture was filtered through celite, washed with ethanol and concentrated to give N-[(E)-2-(4-ethyl-piperazin-1-yl)-penta-2,4-dien-(Z)-ylidene]-methanediamine (377 mg, 86%) as a grey solid.
Reaction SMILES: II.Br[CH2:4][CH:5]1[CH2:7][CH2:6]1.[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:17]2[CH2:18][C@H:19]3[CH2:31][C@H:20]3[C:21]=2[N:22]([C:24]2[CH:29]=[N:28][C:27](Br)=[CH:26][N:25]=2)[N:23]=1)=[O:15])([CH3:12])[CH3:11]>CC(N(C)C)=O.C1COCC1.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:17]2[CH2:18][C@H:19]3[CH2:31][C@H:20]3[C:21]=2[N:22]([C:24]2[CH:29]=[N:28][C:27]([CH2:4][CH:5]3[CH2:7][CH2:6]3)=[CH:26][N:25]=2)[N:23]=1)=[O:15])([CH3:12])[CH3:11]
Reactant: CC(C)(CO)NC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: BrCC1CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(CC3CC3)cn2)c2c1C[C@H]1C[C@@H]21
Temperature: 70 °C
Yield: 7.6 %

Procedure:
Under nitrogen protection, zinc suspension (1.76 mL, 1.338 mmol) was added to a solution of diiodine (4.5 mg, 0.018 mmol) in DMA at room temperature. After several minutes, (bromomethyl)cyclopropane (120 mg, 0.892 mmol) was added. The reaction mixture was heated at 70° C. for 3 h, cooled down to room temperature, then transferred to a flask containing (1aR,5aR)-2-(5-bromo-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (70 mg, 0.178 mmol) and bis(tri-t-butylphosphine)palladium (0) (9.1 mg, 0.018 mmol) in THF (1 mL). The whole reaction mixture was heated at reflux overnight, cooled down and quenched with saturated sodium bicarbonate. The solid was filtered, and the filtrate was extracted with ethyl acetate. The combined organics were dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (5 mg) as white solid. LCMS m/z=368.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46 (td, J=4.7 and 3.3 Hz, 1H), 1.22-1.28 (m, 1H), 1.40 (s, 3H), 1.41 (s, 3H), 1.95-2.04 (m, 1H), 2.09-2.16 (m 1H), 2.26-2.32 (m, 1H), 2.37-2.41 (m, 4H), 2.68-2.74 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.5 and 6.2 Hz, 1H), 3.69 (d, J=6.3 Hz, 2H), 3.72-3.77 (m, 1H), 4.78 (br, 1H), 6.97 (s, 1H), 8.26 (d, J=1.3 Hz, 1H), 9.15 (d, J=1.3 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:11]N(C)C)[CH2:7][N:8]([CH3:10])[CH3:9])=O)C.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)[O-].[Na+]>C(O)(C)C>[CH3:9][N:8]([CH2:7][CH:6]1[CH2:11][N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:22][C:4]1=[O:3])[CH3:10]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(CN(C)C)CN(C)C
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)CC1CN(c2ccccc2)NC1=O

Procedure:
Ethyl-1,3-bis (dimethylamino)-propane-2-carboxylate (20.2g) was added in one portion to a boiling mixture of phenyl-hydrazine (10.8g) and sodium isopropoxide (2.3g of sodium) in isopropanol. The solution was boiled under reflux for 30 minutes and the product (13.6g, 62%) was recovered in a manner similar to that described in Example 16. The product was identified as 4-dimethylaminomethyl-1-phenylpyrazolidin-3-one (melting point 117°-8° C) from its infrared spectrum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([O:26]C)=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccccc1F)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 29 h
Yield: 79.1 %

Procedure:
To methanol (290 mL) solution of the compound obtained in Example 5 (7.1 g) was added dropwise 1 mol/L of an aqueous sodium hydroxide solution (29 mL) at room temperature. The mixture was allowed to stir for 29 hours, and thereafter to the residue obtained by distilling off the solvent under a reduced pressure was added water. The solution was made acidic with dilute hydrochloric acid, and the crystals precipitated were filtered, to give the captioned compound (5.4 g, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]#[N:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[CH2:20]([NH:27][C:28]([NH2:30])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]#[N:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:30][C:28]([NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:29])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2cc(Br)ccc2c1O
Reactant: NC(=O)NCc1ccccc1
Product: CCOC(=O)c1nc(C#N)c2cc(NC(=O)NCc3ccccc3)ccc2c1O

Procedure:
7-(3-Benzyl-ureido)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-bromo-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using benzylurea. MS ESI(+) m/e: 391.0935 (M+1).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:4]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[C:5]=2[S:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[ClH:1].[NH2:2][C:3]1[C:4]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[C:5]=2[S:6][C:7]=1[Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1csc2c1CCCC2=O
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1c(Br)sc2c1CCCC2=O
Reaction time: 0.5 h

Procedure:
To a suspension of 3-Amino-5,6-dihydro-4H-benzo[b]thiophene-7-one hydrochloride (the compound of Preparation Example 6) (1.2 g) in N,N-dimethylformamide (33 mL) was added 1.05 g of N-bromosuccinimide (1.05 g) on an ice bath. After stirring for 30 minutes, the solvent was evaporated at reduced pressure, the pH was adjusted to 10 with an aqueous solution of sodium bicarbonate. After extracting with ethyl acetate, and washing the organic layer with water, drying with anhydrous magnesium sulfate was carried out and the solvent was evaporated at reduced pressure. The residue was dissolved in ethyl acetate, and the pH was brought to 1 by adding 4N hydrochloric acid/ethyl acetate. The resulting solid was collected by filtration, washed with ethyl acetate to provide the title compound (1.55 g) as an ocher solid.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[CH:13]([O:16][CH2:17][CH2:18][OH:19])([CH3:15])[CH3:14]>>[CH:13]([O:16][CH2:17][CH2:18][O:19][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CC(C)OCCO
Product: CC(C)OCCOc1ccc(C(=O)O)cn1
Yield: 51 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 51% yield starting from ethyl 6-chloronicotinate and 2-isopropoxyethanol; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (dd, 1 H), 8.13 (dd, 1 H), 6.91 (dd, 1 H), 4.39-4.43 (m, 2 H), 3.67-3.71 (m, 2 H), 3.55-3.65 (m, 1 H), 1.09 (d, 6 H); MS (APPI/APCI) m/z 226[M+H+].
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=O)=O.[CH3:30][O:31][CH2:32][C:33]#[C:34][Sn](CCCC)(CCCC)CCCC>>[CH2:21]([O:20][C:18]([NH:17][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[C:34]#[C:33][CH2:32][O:31][CH3:30])[C:13]([O:15][CH3:16])=[O:14])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCC[Sn](C#CCOC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Product: COCC#Cc1ccc(C(=O)OC)cc1NC(=O)OCc1ccccc1
Yield: 67.1 %

Procedure:
Methyl 3-benzyloxycarbonylamino-4-(3-methoxy-1-propynyl)benzoate (4.23 g) was prepared from 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (7.73 g) and (3-methoxy-1-propynyl)tributylstannane (6.67 g) in a similar manner to that of Preparation 1 (2).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:11]=[C:10]([CH3:12])[NH:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(O[C:22]([CH3:25])([CH3:24])[CH3:23])(=O)C>C(O)(=O)C>[CH3:6][C:7]1[C:11]([C:22]([CH3:25])([CH3:24])[CH3:23])=[C:10]([CH3:12])[NH:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: CC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C)c(C(C)(C)C)c1C

Procedure:
A solution of acetic acid (5.0 ml), sulfuric acid (1.2 ml), ethyl 3,5-dimethylpyrrole-2-carboxylate 5a (5.0 g, 0.03 mol) and tert-butyl acetate (3.5 g, 0.03 mol) was heated at 75° C. for 2 h and combinedwith sodium carbonate (8 g) in ice water (100 ml) to bring about the precipitation of ethyl 3,5-dimethyl-4-tert-butylpyrrole-2-carboxylate 4g as a colorless solid, mp 108°-110° C. (lit. 107°-109° C.), 3.1 g (47%); 1H NMR (CDCl3): δ 9.80 (s, 1H), 4.28 (q, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 1.35 (s, 9H), 1.33 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][CH2:19][CH:20]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH:20]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:19][CH2:18][CH2:17][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[O:7]3)[CH2:3][CH2:2]2)=[CH:26][CH:25]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: O=C1OC2(CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccccc21

Procedure:
A mixture of 4.0 g. of 1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one, 6.4 g. of 4-chloro-1,1-di(4-fluorophenyl)butane, 10 g. of potassium carbonate, and 25 ml. of 1-butanol is heated under reflux for 48 hours and filtered. The filtrate is diluted with water and extracted with benzene. The benzene solution is dried over potassium carbonate and concentrated to an oil, 1,3-dihydro-1'-[4,4-di(4-fluorophenyl)butyl]spiro[isobenzofuran-1,4'-piperidine]-3-one. The oil is converted to a crystalline hydrochloride salt, m.p. 182°-183° (from benzene).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4].C[O:18][C:19]([CH3:21])=[CH2:20].OS([O-])(=O)=O.[K+]>O>[CH3:1][C:2]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:3][CH:4]=[CH:20][C:19](=[O:18])[CH3:21]
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)C
Reactant: C=C(C)OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: CC(=O)C=CC=C(C)CCCC(C)CCCC(C)C
Temperature: 50 °C
Yield: 7.3 %

Procedure:
190 g of 3,7,11-trimethyldodec-1-yn-3-ol (purity 95%, 0.848 mol) and 200 g of 2-methoxypropene (2.78 mol) and 0.58 g of KHSO4, dissolved in 1.74 g of water, were introduced into a pressure-resistant vessel. The reactor was flushed with nitrogen and closed. After a reaction time of 1 hour at 120° C., the mixture was cooled to about 50° C. and a further 0.58 g of KHSO4, dissolved in 1.74 g of water, was added. The mixture was once again heated to 120° C. After a reaction time of one hour, the reaction was complete. Distillation was carried out as in Example 1.147 g of a mixture comprising mainly 2-methoxypropene and 2,2-dimethoxypropane and 213 g of a fraction comprising 1.6% of 3,7,11-trimethyldodec-1-yn-3-ol, 67% of 6,10,14-trimethylpentadeca-4,5-dien-2-one, and 7.3% of 6,10,14-trimethylpentadeca-3,5-dien-2-one were obtained.
Reaction SMILES: [N:1]1([S:6]([C:9]2[NH:10][C:11](=[O:15])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>ClCCl.C(N(CC)CC)C>[N:1]1([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:10]=2)(=[O:8])=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cccc(S(=O)(=O)n2cccc2)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cccc(S(=O)(=O)n2cccc2)n1

Procedure:
To a stirred solution of 2-(pyrrole-1-sulphonyl)pyrid-6-one (0.22 g) in dichloromethane (20 cm3) under nitrogen at 0° C. was added in solution of mesyl chloride (0.124 g) in dichloromethane (5 cm3) and triethylamine (0.109 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@@:8]12[C:18]3[C:19](S(C4C(C(C)C)=CC(C(C)C)=CC=4C(C)C)(=O)=O)=[CH:20][CH:21]=[C:22]4[NH:23][CH:24]=[C:16]([C:17]=34)[CH2:15][C@H:9]1[NH:10][C:11](=O)[CH2:12][O:13]2>C1COCC1>[CH3:7][C@@:8]12[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[NH:23][CH:24]=[C:16]([C:17]=34)[CH2:15][C@H:9]1[NH:10][CH2:11][CH2:12][O:13]2
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3[nH]cc4c3c2[C@@]2(C)OCC(=O)N[C@@H]2C4)c(C(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12OCCN[C@@H]1Cc1c[nH]c3cccc2c13
Yield: 18.6 %

Procedure:
Lithium aluminum hydride (5 equivalents) was allowed to react with a THF solution (20 ml) of trans-4,6,6a,8,9,10a-hexahydro-10a-methyl-1-(2,4,6-triisopropylphenylsulfonyl)-7H-indolo[3,4-gh][1.4]benzoxazin-8-one (1.2 g, 2.36 mmol). The residue thus obtained was subjected to a silica gel column chromatography, eluting with ethyl acetate, to afford 100 mg (15%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1.Cl.CCOCC>C(O)(C)C>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([Cl:22])=[CH:24][C:25]=3[F:30])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: N#Cc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCc1ccccc1
Yield: 80.5 %

Procedure:
A suspension of 7-benzyloxy-4-chloro-6-cyanoquinoline (2 g, 6.8mmol), 4-chloro-2-fluoroaniline (1.1 g, 7.5 mmol) in isopropanol (50 ml) containing 1M ethereal hydrogen chloride (8 ml) was heated at reflux for 2 hours. After cooling to ambient temperature ether was added. The precipitate was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-cyanoquinoline hydrochloride (2.41 g, 81%).
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][N:6]1[N:10]=[CH:9][CH:8]=[N:7]1)C.O.[NH2:13][NH2:14]>C(O)C>[N:10]1[N:6]([CH2:5][C:4]([NH:13][NH2:14])=[O:11])[N:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cn1nccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)Cn1nccn1
Temperature: 25 °C
Yield: 68 %

Procedure:
As described for example 112a, [1,2,3]triazol-2-yl-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture heated under reflux for 3 h. The mixture was cooled to rt and the precipitated product was filtered off and dried to afford the title compound as a white solid (yield: 68%). MS: m/e=141.1 [M]+.
Reaction SMILES: C([O:8][C:9](=[O:29])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:18]2)=[C:13]([F:28])[CH:12]=1)C1C=CC=CC=1.[CH3:30][C:31](C)([O-:33])C.[Li+]>C(OCC)(=O)C>[F:28][C:13]1[CH:12]=[C:11]([N:10]2[CH2:13][C@H:12]([CH2:11][NH:10][C:31](=[O:33])[CH3:30])[O:8][C:9]2=[O:29])[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:18]1
Reactant: O=C(Nc1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1)OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3ccc(-c4ccccn4)n3)c(F)c2)C(=O)O1
Yield: 91.5 %

Procedure:
The above-described product 20a (1.235 g, 3.18 mmol) and lithium tert-butoxide (0.762 g) were mixed in a reaction vessel. After the air in the vessel was purged with nitrogen, tetrahydrofuran (5 mL) was added into the vessel and the mixture was cooled in an ice-water bath for 5 minutes. Then, methanol (0.204 g, 0.258 mL) was added. Two minutes later, a solution of Compound (11) (1.237 g) in tetrahydrofuran (5 mL) was added. Then, the water-ice bath was removed and the resultant mixture was reacted for 14 hours at room temperature. After completion of the reaction, ethyl acetate was added to the reactant mixture, resulting in a substantial amount of precipitate. Thus obtained mixture was suction-filtered, and the filter cake was recrystallized with a solvent mixture of ethyl acetate/petroleum ether to afford the product 12a (575 mg) as a white powder, with a yield of 45.7%.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH3:28])[CH:19]=2)=[O:16])[CH2:8][CH2:7]1)=[O:5])C.[ClH:29]>>[ClH:29].[ClH:29].[CH3:28][C:20]1[CH:19]=[C:18]([NH:17][C:15](=[O:16])[NH:14][CH2:13][CH2:12][N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: CCOC(=O)C1CCN(CCNC(=O)Nc2cc(C)nc3ccccc23)CC1
Agent: Cl
Product: Cc1cc(NC(=O)NCCN2CCC(C(=O)O)CC2)c2ccccc2n1
Temperature: 50 °C

Procedure:
1-{2-[3-(2-Methyl-quinolin-4-yl)-ureido]-ethyl}-piperidine-4-carboxylic acid ethyl ester (0.9 g, 2.3 mmol) is dissolved in 6N aqueous HCl (10 mL) and the mixture is heated at 50° C. for 48 h. The reaction mixture is evaporated and the residue is dried to provide the title compound as hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[O:11].[CH4:13].CS(O)(=O)=O>C(Cl)Cl>[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:13]1[CH:7]=[CH:6][C:5]([N:10]=[O:11])=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=1)[OH:11])([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1ccccc1N=O
Reactant: C
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(N(O)c2ccccc2C(=O)OC)ccc1N=O
Reaction time: 1 h
Yield: 43.6 %

Procedure:
8.2 g (50 mmol) of 2-nitroso-benzoic acid methyl ester were dissolved in 50 ml of methylene chloride and 7.2 g (75 mmol) of methane solufonic acid added thereto at 0° C. Upon addition of the methane sulfonic acid, the green solution turned dark red. During the entire duration of the reaction the temperature of the reaction mixture did not exceed 10° C. After 1 hour (as described in detail in previous Examples), the solution was sprayed onto water under a vacuum and the methylene chloride removed at the same time. By means of filtration it was possible to obtain 3.6 g (44% of theoretical) of N-(2-carbomethoxyphenyl)-N-(3-carbomethoxy-4-nitrosophenyl)-hydroxylamine in the form of a beige powder (decomposition from 85° C. on), the identity of which was ascertained by means of elementary analysis, titration and spectra (NMR, UV, IR).
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:18][C:17]=1[Cl:26])=[N:5]/[O:6][CH3:7].[CH3:28][NH2:29]>CO>[Cl:26][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[Cl:24])[CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1/[C:4](=[N:5]\[O:6][CH3:7])/[C:3]([NH:29][CH3:28])=[O:2]
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1ccc(C=C(Cl)Cl)cc1Cl
Reactant: CN
Solvent: CO
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc(C=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.8 %

Procedure:
Methyl-(E)-2-(2-((2-chloro-4-(2,2-dichlorovinyl)phenoxy)methyl)phenyl)-2-methoxyiminoacetate (0.428 g, 1 mmol) obtained in Example 39 was added to 10 ml of methanol. 40% methylamine solution (0.39 g, 5 mmol) was slowly added thereto, and the mixture was stirred at room temperature for 6 hours. The solvent was removed therefrom under a reduced pressure. After adding water thereto, the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate:n-hexane=1:4) to obtain the title compound (0.38 g, 89%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH:19]=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]1([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH2:19][N:30]3[CH2:31][CH2:32][CH:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: c1ccc(CN2CC(CN3CCC(c4ccccc4)CC3)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A solution of 680 mg (2.6 mmol) of 1-phenylmethyl -3-(RS)-formyl -4-(SR)-phenylpyrrolidine (from Example 9, Step B) and 420 mg (2.6 mmol) of (4-phenyl)piperidine in 25 mL of dichloroethane at 0° C. was treated with 635 mg (3.0 mmol) of sodium triacetoxy-borohydride. The cooling bath was removed and the resulting mixture was stirred at rt for 2h. The reaction mixture was partitioned between 100 mL of EtOAc and 50 mL of sat'd NaHCO3 and the layers were separated. The organic layer was washed with 50 mL of sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 50 g of silica gel using 10:1 v/v hexanes/EtOAc+1% TEA as the eluant afforded 1.01 g of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ1.65-2.02 (6H.), 2.42-3.03 (11H), 3.72 (AB q, J=35.4, 2H), 7.20-7.43 (m, 15H). Mass Spectrum (NH3 -CI): 411 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=3)[S:16][C:10]=2[NH:11][C:12](=[S:42])[CH2:13][N:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Cc1ccc(CCCCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(CCCCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 143.1 %

Procedure:
A suspension of 8.9 g of 5-(2-chlorophenyl)-7-[4-(4-isobutylphenyl)butyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 133°-135° C. and 4.7 g of Lawesson reagent in 100 ml of toluene is stirred at 38°-40° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 8 g of 5-(2-chlorophenyl)-7-[4-(4-isobutylphenyl)butyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 169°-171° C. with decomposition.