Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[CH:27]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][C@@H:24]([O:41][CH2:42][CH3:43])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH:27]([C@@H:28]([OH:40])[C@@H:29]([NH:39][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=2)[CH2:26][O:25][C@@H:24]([O:41][CH2:42][CH3:43])[CH2:23]1)=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCO[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCO[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)CO1
Reaction time: 4 h

Procedure:
Add triethylamine (0.030 g, 0.30 mmol) and acetic anhydride (0.024 g, 0.23 mmol) to (R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-ethoxymorpholine-4-carboxylic acid tert-butyl ester (0.095 g, 0.228 mmol) in tetrahydrofuran (4 mL) at room temperature. Stir 4 hours and dilute with ethyl acetate. Wash with water and saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify on silica gel, eluting with 20:80 to 100% ethyl acetate:hexanes to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][S-:32].[Na+]>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:25]=[N:26][C:27]([S:32][CH3:31])=[CH:28][CH:29]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(Cl)nc2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Temperature: 70 °C

Procedure:
4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (231 mg, 0.5 mmol) was dissolved in dry THF (5 mL) and treated with sodium thiomethoxide (175 mg, 2.5 mmol) and the mixture was heated at 70° C. for 4 h. The solvent was evaporated and the residue suspended in water (5 mL) and the product was precipitated by the drop wise addition of 3M HCl and purified by HPLC. 1H-NMR (400 MHz, CDCl3): δ 1.19 (s, 9H), 2.60 (s, 3H), 7.21-7.28 (m, 3H), 7.31 (m, 1H), 7.50-7.54 (m, 3H), 7.65 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.78 (d, 1H, J=8.8 Hz), 8.19 (m, 1H), 9.62 (s, 1H). MS: m/z 476.0 (M++1).
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3]([NH:5][NH2:6])=O.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>Cl.CO>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]2[N:5]([C:3]([C:2]([F:17])([F:1])[C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[N:13]=[CH:12][CH:11]=[CH:10]4)=[N:20][N:21]=2)[N:6]=1
Reactant: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Solvent: CO
Product: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12
Temperature: 90 °C

Procedure:
A suspension of 2,2-difluoro-2-(quinolin-6-yl)acetohydrazide (2000 mg, 8432 μmol) and 3,6-dichloropyridazine (3768 mg, 25295 μmol) in 1.25 M HCl in MeOH (20 mL) was heated to 90° C. with microwaves for 50 min. The solvents were then removed under reduced pressure and residue partitioned between 9:1 CHCl3/IPA (60 mL) and 1 M NaOH (20 mL). The organic phase then dried over MgSO4, concentrated, then purified on silica (120 g) eluting with 1>2.5% of 2 M NH3 in MeOH/DCM to provide product isolated as a dark tan soild. MS (ESI pos. ion) m/z: 332 (MH+). Calc'd exact mass for C15H8ClF2N5: 331.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=O.Cl.[CH3:23][NH:24][CH3:25].Cl>C(O)(C)C.C(O)C>[C:1]1([C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH2:13][CH2:23][N:24]([CH3:20])[CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1c(-c2ccccc2)oc2c(C)cccc12
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: Cc1cccc2c(C(=O)CCN(C)C)c(-c3ccccc3)oc12

Procedure:
To a suspension of 10 grams of the 2-phenyl-3-acetyl-7-methylbenzofuran that was thus prepared in 40 milliliters of isopropanol was added 1.7 grams of paraformaldehyde, 4.6 grams of dimethylamine hyrochloride, and 4 milliliters of a saturated solution of hydrogen chloride in ethanol, and the mixture was heated at its boiling point for a period of 10 hours. The solvent was then evaporated from the mixture under vacuum and the residue was taken up in water, and the insoluble portions of the residue were extracted from the resulting solution with ethyl ether. The aqueous solution was then made alkaline by the addition thereto of a 5% aqueous solution of sodium hydroxide and the precipitated base was extracted therefrom by the addition of ethyl ether thereto. The ethyl ether extract was separated and dried over anhydrous sodium sulfate. A solution of hydrogen chloride in ethanol was then added to the dried ether extract, whereupon crystals of the hydrochloride of the compound named in the heading of this example precipitated therefrom. The crystals were separated by suction filtration and recrystallized from a mixture of ethanol and ethyl ether. In this manner, 13.2 grams of crystals of the hydrochloride, having a melting point of 145°-146.5° C, was obtained.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[NH:36][NH2:37])[CH:29]=[CH:28][CH:27]=1>>[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc2cccnc12
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2cccnc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and quinolin-8-yl-hydrazine according to the method described for example 43. MS: M=450.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:17]([NH:25][C:26]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nc(-c2ccc3c(c2)CCCC3)cs1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1nc(-c2ccc3c(c2)CCCC3)cs1)c1ccccc1
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A mixture consisting consisting of 2-amino-4-(5,6,7,8-tetrahydro-2-naphthyl)thiazole (500 mg), benzoylisothiocyanate (363 mg) and acetone (10 ml) was stirred at 55° to 60° C. for 3 hours and then concentrated under reduced pressure. The residue was treated with ether, and the resultant crystals were recrystallized from chloroform-ethanol to produce 1-benzoyl-3-[4-(5,6,7,8-tetrahydro-2-naphthyl)-2-thiazolyl] thiourea (yield of 583 mg, 68.2%) in the form of colorless prisms. m.p., 181°-182° C.
Reaction SMILES: [Na:1].[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[O:6])[CH3:3].[C:18](O)(=[O:23])[CH2:19][C:20](O)=[O:21].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:2]([N:4]1[C:18](=[O:23])[CH2:19][C:20](=[O:21])[N:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[C:5]1=[O:6])[CH3:3].[Na:1]
Reactant: O=C(O)CC(=O)O
Reactant: CCNC(=O)Nc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCN1C(=O)CC(=O)N(c2ccc(S(=O)(=O)O)cc2)C1=O
Temperature: 95 °C
Yield: 93.5 %

Procedure:
A mixture of 26.6 g of N-ethyl-N'-(4-sulfophenyl)urea sodium salt, 13.5 g of malonic acid and 150 ml of glacial acetic acid was heated and dissolved at 60° to 70° C. Acetic anhydride (200 ml) was added dropwise to the solution with stirring. After addition of the acetic anhydride, the temperature of the reaction solution increased to 95° C. The reaction solution was stirred for 6 hours and then condensed under reduced pressure so as to precipitate crystals. 700 ml of ethanol was added to the condensed solution and the crystals were completely precipitated. The precipitated crystals were collected by filtration, washed thoroughly with ethanol and dried by heating under reduced pressure to obtain 31.2 g of crystals. The crystals obtained were recrystallized using a 90% methanol aqueous solution and, thereby, 23.5 g of white crystals was obtained. Melting point: 290° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH2:19][CH3:20]>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:19][CH3:20]
Reactant: COC(=O)c1ccccc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccccc1C(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of methyl 2-hydroxybenzoate (1.05 g) and potassium carbonate (1.43 g) in dimethylformamide (10 ml) was added propyl iodide (1.41 g) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with 1N sodium hydroxide solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1) to give methyl 2-(propyloxy)benzoate as colorless oil (853 mg).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH2:11][CH:12]1[CH2:14][C:13]1([Cl:16])[Cl:15].C[O-].[Na+].[Cl:20][C:21](OC(Cl)(Cl)Cl)=[O:22]>O.C(Cl)(Cl)Cl.CO>[Cl:20][C:21]([O:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([O:10][CH2:11][CH:12]2[CH2:14][C:13]2([Cl:15])[Cl:16])[CH:5]=1)=[O:22]
Reactant: Oc1ccc(Cl)c(OCC2CC2(Cl)Cl)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: O=C(Cl)Oc1ccc(Cl)c(OCC2CC2(Cl)Cl)c1

Procedure:
The sodium salt of 4-chloro-3-[(2,2-dichlorocyclopropyl)methoxy]phenol as prepared from 20 g of 4-chloro-3-[(2,2-dichlorocyclopropyl)methoxy]phenol and 16 g of a 28% methanol solution of sodium methylate was dissolved in 300 ml of water and the solution was added dropwise to a solution of 5 ml of trichloromethyl chloroformate in 100 ml of chloroform while maintaining the reaction temperature at 10° C. or below. The reaction mixture was allowed to stand for phase separation. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was then distilled off. There was obtained 22.5 g of 4-chloro-3-[(2,2-dichlorocyclopropyl)methoxy]phenyl chloroformate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH:3]([CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:8]1)[CH2:4][OH:5].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[CH:3]([CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[CH2:8]1)[CH2:4][O:5][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC(CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
In a 50 mL round-bottomed flask, 3,3,3-trifluoro-2-((2-(3-(trifluoromethyl)phenyl)morpholino)-methyl)propan-1-ol (760 mg, 2.13 mmol) was combined with CH2Cl2 (10.0 ml) to give a colorless solution and then cooled to 0° C. DIPEA (412 mg, 557 μl, 3.19 mmol) and methanesulfonyl chloride (244 mg, 166 μl, 2.13 mmol) were added dropwise and the resulting reaction mixture was stirred for 30 min. The reaction was diluted with CH2Cl2 (30 ml), washed with sat. NaHCO3 solution followed by washing with H2O, dried over MgSO4, filtered and concentrated to give 880 mg (95%) of methanesulfonic acid 3,3,3-trifluoro-2-[2-(3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-propyl ester as a colorless oil. MH+=436.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18][CH2:19][C:20]([NH2:22])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18]([CH2:19][C:20]([NH2:22])=[O:21])=[O:31])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC(=O)CSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: NC(=O)CS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
2-{[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio}acetamide (0.12 g, 0.36 mmol) was dissolved in chloroform (300 ml), and a solution of 3-chloroperbenzoic acid (77%, 0.082 g, 0.36 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.071 g, 57%) as white crystals.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6]1([CH3:12])[CH:11]=[CH:10]C=CC=1.[OH:13][C:14]1[C:17](=O)[C:16](=[O:19])[C:15]=1[OH:20]>O>[CH2:1]([O:5][C:17]1[C:14](=[O:13])[C:15](=[O:20])[C:16]=1[O:19][CH2:10][CH2:11][CH2:6][CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1
Reactant: CCCCO
Reactant: O=c1c(O)c(O)c1=O
Solvent: O
Product: CCCCOc1c(OCCCC)c(=O)c1=O

Procedure:
A mixture of 1-butanol (3 L), toluene (2 L) and 1,2-dihydroxy-1-cyclobutene-3,4-dione (1 kg; 8.767 moles) was refluxed with stirring under a Dean-Stark separator until water stopped passing over (theory:0.316 L). The excess toluene and butanol were then removed by distillation under reduced pressure to give the title compound as a yellow liquid. The concentrate was diluted with methanol (1.5L) and used in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]#N)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][CH:22]=1.C([O:27]CC)C>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=2)=[O:27])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Reactant: CCOCC
Product: O=C(c1cccc(F)c1)C1CN(Cc2ccccc2)CCO1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 4-Benzyl-morpholine-2-carbonitrile (10 g, 50 mmol) in dry diethyl ether (100 ml) at −10° C. under an atmosphere of nitrogen was added (time of addition 30 minutes) a solution of 3-fluorophenylmagnesium bromide (0.5N solution in tetrahydrofuran, 120 ml, 60 mmol, 1.2 equivalents, available from Aldrich Chemical Company or Rieke Metals) and the reaction mixture was further stirred at −10° C. for 30 minutes. Then the reaction was allowed to warm to room temperature and stirred for one hour. The reaction was then cooled to 0° C. and quenched by addition of hydrochloric acid (2N aqueous solution, 50 ml) and the resulting mixture was stirred for 30 minutes at 0° C. Then the solution was concentrated in vacuo and the residue was taken-up by sodium hydroxide (2N aqueous solution, 60 ml). The aqueous solution was extracted with diethyl ether, the organics fractions were collected and dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as a brown oil (15 g, 100%). FIA [M+H]+=300.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[OH:22][C:23]1C(C)=CC(C#N)=CC=1OC.CC1(C)O[C@H](CO)CO1>>[CH3:21][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[O:22][CH3:23])[CH2:4][O:3]1
Reactant: COc1cc(C#N)cc(C)c1O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Agent: CC1(C)OC[C@@H](CO)O1
Product: COc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a beige oil (1.16 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 4-hydroxy-3-methoxy-5-methyl-benzonitrile and L-α,β-isopropylidene glycerol. LC-MS: tR=0.65 min, [M+H]+=311.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH:22]=[N:21][C:20]([C@@:23]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[OH:24])=[N:19]2)[CH2:13][CH2:12]1.[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C@@H:56]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:57]Br)=[C:49]2[C:54]=1[NH:53][C:52](=[O:55])[CH:51]=[CH:50]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+]>C(#N)C>[NH3:1].[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C@@H:56]([O:59][Si:60]([C:63]([CH3:64])([CH3:66])[CH3:65])([CH3:62])[CH3:61])[CH2:57][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][N:18]3[CH:22]=[N:21][C:20]([C@:23]([CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)([OH:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:19]3)[CH2:15][CH2:16]2)=[C:49]2[C:54]=1[NH:53][C:52](=[O:55])[CH:51]=[CH:50]2)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: NCCCCCCCCCN1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCCCCN1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: N
Temperature: 90 °C
Reaction time: 72 h

Procedure:
(R)-(1-{[1-(9-aminononyl)piperidin-4-yl]methyl}-1H-1,2,4-triazol-3-yl)(cyclohexyl) phenylmethanol (Preparation 6, 350 mg, 0.706 mg), 8-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]quinolin-2(1H)-one (WO200509286, 345 mg, 0.706 mmol) and sodium hydrogen carbonate (88.9 mg, 1.06 mmol) were combined in acetonitrile (7 mL). After stirring at 90° C. for 72 hours the solvent was removed in vacuo and residue partitioned between dichloromethane (50 ml) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (99:1:0.1 to 95:5:0.5 by volume) to furnish the title compound as a clear glass, in 37% yield, 240 mg (contains 10% of other triazole regio-isomer).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1[Cl:13].[CH3:14][S:15]([CH2:18][C:19]#[N:20])(=[O:17])=[O:16].C(N(CC)CC)C>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[C:19]#[N:20])=[C:3]1[Cl:13]
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Reactant: CS(=O)(=O)CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(Cl)c(C=C(C#N)S(C)(=O)=O)c2ccccc21
Reaction time: 144 h

Procedure:
To 550 mg of 1-methyl-2-chloroindole-3-carbaldehyde, dissolved in 25 ml of THF, was added 730 mg of methylsulfonylacetonitril and 1.2 g of triethylamine. After 24 hours another 300 mg of methylsulfonylacetonitril was added, and the mixture was stirred for 6 days. The precipitate was collected by filtration to give (3a). Yield 630 mg of (3a), m.p. 180° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)[Si](OC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.4 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.12 g, 4.71 mmol) (obtained as described in Reference Example 62(1)) in methanol (106 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide (2.12 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (100 ml). To the mixture were added benzenesulfonyl chloride (0.90 g, 7.07 mmol) and triethylamine (0.98 ml, 7.07 mmol) in an ice bath, and the mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]azetidine (755 mg, yield 28%) as pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20]N=2)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.ClC1[C:31]([O:32][CH3:33])=CN=C2NC=CC=12.C(OC(N1CCNCC21CC2)=O)(C)(C)C>>[CH2:10]1[C:9]2([CH2:12][N:13]([C:16]3[C:31]([O:32][CH3:33])=[CH:20][N:19]=[C:18]4[NH:22][CH:23]=[CH:24][C:17]=34)[CH2:14][CH2:15][NH:8]2)[CH2:11]1
Reactant: COc1cnc2[nH]ccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: CC(C)(C)OC(=O)N1CCNCC12CC2
Product: COc1cnc2[nH]ccc2c1N1CCNC2(CC2)C1

Procedure:
Prepared in a sequence similar to the sequence described for intermediates 1 and 2, starting from 4-chloro-5-methoxy-1H-pyrrolo[2,3-b]pyridine and 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester.