Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]1([C:37]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:38]2[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45]O)[N:40]=[CH:39]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:53]1([C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:38]2[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][O:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=3)[N:40]=[CH:39]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(OCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.08 h

Procedure:
5 ml of tetrahydrofuran, 129 mg (0.8 mmol) of 4-trifluoromethylphenol and 209 mg (0.8mmol) of triphenylphosphine are added, under nitrogen, to 280 mg (0.76 mmol) of 1-triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole. The resulting mixture is stirred for 5 min. 139 mg (0.8 mmol) of diethyl azodicarboxylate in 5 ml of tetrahydrofuran are then slowly added. Stirring is continued at room temperature for 3 hours under nitrogen. The solvent is then evaporated and the residue is then chromatographed on a column of silica gel (first eluent petroleum ether containing increasing amounts of diethyl ether up to 100%) to give the monohydrate of 1-triphenylmethyl-4-[3-(4-trifluoromethylphenoxy)propyl]-1H-imidazole which is crystallized from ethanol, M.p.: 150°-151° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14].[OH-].[Na+].C(O)=O>CO>[CH3:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:14])([F:15])[F:16]
Reactant: COC(=O)c1c[nH]c(-c2ccccc2C(F)(F)F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: Cc1c(C(=O)O)c[nH]c1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 83.4 %

Procedure:
Methyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (1.4 g, 4.9 mmol) was dissolved in methanol (12 mL), and a 5 M aqueous sodium hydroxide solution (10 mL) was added thereto, and the resulting mixture was heated under reflux for 3 hours. After the mixture was cooled to room temperature, formic acid (5 mL) was added thereto to stop the reaction. After the mixture was concentrated under reduced pressure, water (10 mL) was added thereto to suspend the resulting residue. The precipitated solid was collected by filtration and washed times with water. The obtained solid was dried under reduced pressure, whereby 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (1.1 g, 83%) was obtained as a solid. The thus obtained solid was suspended in dichloromethane (10 mL), oxalyl chloride (0.86 mL, 10 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 2 hours. After the mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL), and 4-(methylsulfonyl)aniline hydrochloride (1.0 g, 4.9 mmol) and N,N-diisopropylethylamine (2.8 mL, 16 mmol) were sequentially added to the solution, and the resulting mixture was heated under reflux for 18 hours. After the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and acetonitrile (10 mL) and 3 M hydrochloric acid (100 mL) were added to the residue. A precipitated solid was triturated, collected by filtration and washed with water, and then, dried under reduced pressure, whereby 4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (1.4 g, 89%) was obtained as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([C:8]2[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=2[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[N:4]=[N:5][N:6]([C:8]2[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=2[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-n1cc(CO)nn1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccccc1-n1cc(C=O)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of tert-butyl 2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)benzylcarbamate, 13, (2.5 g, 8.31 mmol) in CH2Cl2 (10 mL) was added MnO2 (5.0 g, 57.5 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude reaction mixture was then filtered through a plug of Celite® and then concentrated in vacuo. The crude material was purified by silica gel chromatography (0-5% methanol/dichloromethane) yielding 610 mg (25%) of 14: ESI+ MS: m/z (rel intensity) 225 (100, M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[OH:19][CH:20]1[CH2:23][NH:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:19][CH:20]1[CH2:23][N:22]([C:15](=[O:17])[CH2:14][NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[CH2:21]1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Reactant: OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CC(O)C1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]acetic acid (30 mg, 0.12 mmol), 3-hydroxyazetidine hydrochloride (13 mg, 0.12 mmol) and HOBt (16 mg, 0.12 mmol) were dissolved in DMF (3 ml) and DIPEA (4311, 0.25 mmol). After 5 min, EDCI (30 mg, 0.15 mmol) was added and the reaction mixture stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 ml) and DCM (3×20 ml). The combined organics were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol:dichloromethane (1:24) to give the title compound as a white solid. δH (CD3OD): 4.06-4.15 (3H, m), 4.40-4.46 (1H, m), 4.55-4.63 (1H, m), 4.77-4.94 (2H, m), 7.14 (1H, s), 7.71 (1H, s), 8.62 (1H, s); RT=2.82 min.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[C:6]([NH:9][C:10]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:12]1[CH:13]=[NH+:14][CH:15]=[CH:16][CH:17]=1)(=[O:8])[CH3:7].F[B-](F)(F)F.[H+].O=O.[H][H]>CO>[F:1][B-:2]([F:5])([F:4])[F:3].[C:6]([NH:9][C@H:10]([C:18]([O:20][CH3:21])=[O:19])[CH2:11][C:12]1[CH:13]=[NH+:14][CH:15]=[CH:16][CH:17]=1)(=[O:8])[CH3:7]
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccc[nH+]c1)NC(C)=O
Agent: F[B-](F)(F)F
Agent: O=O
Agent: [H+]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc[nH+]c1)NC(C)=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
In an autoclave, 3-(2-acetylamino-2-methoxycarbonylvinyl)pyridinium tetrafluoroborate (10.3 kg, 33.44 mol) was dissolved in methanol (120.0 l). Tetrafluoroboric acid solution (50% in water, 1.018 kg, 5.8 mol) was added, and the autoclave was closed and carefully inertized using nitrogen. The catalyst solution was prepared by treating methanol (3.0 l) in an ultrasonic bath for 15 min while introducing argon. With exclusion of air, the methanol degassed in this manner was admixed with (+)-phenyl-CAPP (12.5 g, 20.83 mmol) and [Rh(COD)Cl]2 (5.0 g, 10.10 mmol), and the yellow-orange catalyst solution was sonicated under argon for 30 min. With exclusion of oxygen, the catalyst solution was introduced into the autoclave. Within a period of 1 h, the contents of the autoclave was heated to 40° C. In each case about 3 bar of hydrogen were applied three times, and the autoclave was vented immediately again. 1.5 bar of hydrogen were then applied, and the mixture was hydrogenated at 50° C., with vigorous stirring. After 7 h, the hydrogenation stopped. The HPLC analysis of a sample taken showed that, at this point in time, 99.1% of the title compound was present, and GC analysis (30 m fused silica capillary column Chirasil Val, isothermic 160° C., injector 220° C., detector (FID) 260° C., carrier gas 0.8 bar of hydrogen, tret [(R) enantiomer] 12.64 min, tret [(S) enantiomer] 13.64 min) showed that the enantiomeric purity was 86% ee of (S) isomer. The autoclave was flushed with nitrogen and, using nitrogen, the contents of the autoclave were pressed through a Seitz filter into a vessel, where the filtrate was stored at +5° C. under nitrogen.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([NH:12]C(=O)C(F)(F)F)=[C:5]([CH3:19])[CH:4]=1)#[N:2].N>CO>[NH2:12][C:6]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:19]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Agent: N
Solvent: CO
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of N-(4-cyano-2-methyl-6-nitro-phenyl)-2,2,2-trifluoro-acetamide (5 g, 18.3 mmol) and 2 M ammonia in methanol (80 mL) was heated to reflux for 14 h and then cooled to room temperature. After concentration in vacuo, the residue was purified by flash chromatography (20% EtOAc/hexane) to yield the title compound (3.24 g, 100%, ca 80% pure). 1H NMR (300 MHz, CDCl3) δ 8.40 (1H, s), 7.47 (1H, s), 6.6–6.8 (2H, broad s), 2.89 (3H, s).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:21][C@@H:22]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=425.0 [M+H]+.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:19][CH2:20][C:21]([CH2:25]O)([CH2:23][OH:24])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:19][CH2:20][C:21]1([CH3:25])[CH2:23][O:24][C:11]2([CH2:12][C:13]([CH3:14])([CH3:15])[N:8]([O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]([CH3:18])([CH3:17])[CH2:10]2)[O:16][CH2:22]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reactant: CC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(CO)COC2(CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)OC1

Procedure:
The title compound is prepared from by the reaction of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one and 1,1,1-tris(hydroxymethyl)ethane in the presence of p-toluenesulfonic acid.
Reaction SMILES: [CH:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[N:6]1)([CH2:3][CH3:4])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][N+:13]([O-:30])=[CH:14][CH:15]=2)[C:7]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[N:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(C)n1cc(-c2ccncc2)c(-c2ccc(Cl)s2)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)n1cc(-c2cc[n+]([O-])cc2)c(-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (1 eq, 7.2 mmol) in 23 mL of dichloromethane was added metachloroperbenzoic acid 70% (1.5 eq, 10.9 mmol) in small portion at 0° C. The reaction was then stirred at room temperature overnight. Sodium sulfite (1.5 eq, 10.9 mmol) was then added and the organic layer was then washed with a 2M solution of potassium carbonate, dried over MgSO4, filtered and concentrated to afford 2.25 g of 4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine N oxide (83% yield) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[C:19](Cl)(Cl)=[O:20]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]=[C:19]=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Oc2ccc3ccccc3c2)cc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Oc2ccc3ccccc3c2)cc1
Yield: 92.3 %

Procedure:
A solution of 4-(2-naphthyloxy)aniline (4 g) in toluene (100 ml) was dropwise added to a solution of phosgene (3.5 g) in toluene (50 ml), and the resulting mixture was refluxed for 1 hour. After removal of the solvent from the reaction mixture by distillation under reduced pressure, the residue was distilled in vacuo to give 4-(2-naphthyloxy)phenyl isocyanate (4.1 g) as a fraction boiling at 137° to 149° C./0.8 mmHg. M.P., 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([F:26])([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[N+:23]([O-:25])=[O:24])[C:9]([O:11]C)=[O:10])[CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([F:26])([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[N+:23]([O-:25])=[O:24])[C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COC(=O)C(F)(c1cc(Cl)ccc1OC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cl)cc1C(F)(C(=O)O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 96.1 %

Procedure:
In a 3-necked 5-L round-bottomed flask, equipped with a mechanical stirrer and thermocouple, was suspended 5-chloro-α-fluoro-2-methoxy-α-[2-nitro-4-(trifluoromethyl)phenyl]benzeneacetic acid, methyl ester (450 g, 1.067 mol) in methanol (2.0 L) and 1.0 N aqueous sodium hydroxide (1.10 L, 1.10 mol). The reaction mixture was stirred for 4.5 hours at about 50° C. to complete the hydrolysis (determined by HPLC analysis). The reaction mixture was cooled to room temperature and concentrated on a rotary evaporator to remove most of the methanol. The residue was partitioned between tert-butylmethylether/hexane (1.2 L/0.5L) and water (1.4 L) and extracted. The organic layer was back-extracted with water (500 mL). The combined aqueous layers were cooled in an ice bath and while stirring vigorously, acidified with concentrated hydrochloric acid to about pH 1 (about 110 mL). Preferably, seed crystals of the title compound were added resulting in crystallization/precipitation of the product. The material was filtered after stirring for 3 hours at 0° C., air and vacuum dried overnight to afford 418.1 g of the title compound (96% yield when corrected for solvent, 99.6% by HPLC). A sample was recrystallized from toluene/hexane (1:1.25 at about 5 mL/g) to afford pure title compound.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[O:23].C1(C)C=CC=CC=1>O1CCCC1>[OH:23][CH:22]([C:13]1[S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:21]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C=O
Reactant: c1ccc(-c2csc3ccccc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of butyllithium (1.6 M, 3.75 mL, 6 mmol) was added at −20° C. to a solution of 3-phenyl-1-benzothiophene (3a) (1.18 g, 5.61 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere. After 1 hour, a solution of ethyl glyoxylate in toluene (50%, 1.2 mL, 6 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 hours, quenched with water (5 mL) and concentrated in vacuo. The residue was partitioned between dichloromethane (40 mL) and water (15 mL). The organic layer was washed with water (2×15 mL), brine (15 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired alcohol (3b) as a white solid (340 mg, 1.09 mmol, 20%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[CH2:10][C:11]#[N:12])[CH:5]=[C:6]([F:8])[CH:7]=1.CSC.B.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:13]
Reactant: N#CCC(O)c1cc(F)cc(Br)c1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: NCCC(O)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(3-bromo-5-fluorophenyl)-3-hydroxypropanenitrile (2.50 g, 8.65 mmol) in THF (16.0 mL) was added borane methyl sulfide (1.20 g, 15.7 mmol). The mixture was heated to reflux for 2 h. After cooling to room temperature, saturated aqueous NaHCO3 (10 mL) was added and the mixture was stirred for 1 h. The THF was removed under reduced pressure and the remaining aqueous portion was extracted with ethyl acetate (2×60 ml). The extract was dried (Na2SO4) and concentrated to give 3-amino-1-(3-bromo-5-fluorophenyl)propan-1-ol that was used in following reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].O[CH2:14][NH:15][C:16](=[O:20])[CH:17]([Cl:19])[Cl:18]>>[CH2:1]([C:3]1[C:12]2[C:7](=[C:8]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([Cl:19])[Cl:18])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1nccc2ccccc12
Reactant: O=C(NCO)C(Cl)Cl
Product: CCc1nccc2c(CNC(=O)C(Cl)Cl)cccc12

Procedure:
1-Ethylisoquinoline and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to afford 1-ethyl-5-dichloroacetylaminomethylisoquinoline. The product was reacted successively in the same way as in steps (c), (d), (e) and (f) of Example 18 to afford 1-ethylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-ethylisoquinoline-5-acetic acid having a melting point of 166.2° to 180.8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][O:10][CH:11]([CH:33]=[CH2:34])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].Cl.[NH2:42][OH:43]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:9][O:10][CH:11]([CH2:12][O:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:33]1[CH2:34][O:43][NH:42]2
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)c1ccccc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Fc1ccccc1C12COC(COC(c3ccccc3)(c3ccccc3)c3ccccc3)C1CON2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A reactor was charged with 1-(2-fluorophenyl)-2-((1-(trityloxy)but-3-en-2-yl)oxy)ethanone (61.2 g, 1.0 equiv), toluene (428 mL) and sodium acetate (16.1 g, 1.5 equiv). Upon complete addition, the reaction mixture was stirred at ambient temperature for 5 minutes. Hydroxylamine hydrochloride (10.0 g, 1.1 Eq) was added and the suspension was heated to 111° C. After stirring for >20 hours at 111° C., the reaction mixture was allowed to cool down to ambient temperature, and the suspension was filtered and the solids rinsed with toluene (245 mL) and then THF (10 volumes) The filtrate was concentrated under reduced pressure (bath temp. ≦40° C.) and chased with 2-propanol (275 mL) 2-Propanol (428 mL) was added to the solids and the suspension was heated to 83° C. After stirring for 1 hour at 83° C., the mixture was allowed to cool down to ambient temperature. The slurry was cooled to 0° C. over a 1 hour period and stirred at 0° C. for 1 hour. The suspension was filtered and the solids rinsed in two portions with cold 2-propanol (490 mL) to give 6a-(2-fluorophenyl)-4-((trityloxy)methyl)hexahydrofuro[3,4-c]isoxazole (42.3 g) as a solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@H:4]([C:5]3[CH:16]=[N:15][NH:14][C:6]=3[C@H:7]2[C:10]([O:12][CH3:13])=[O:11])[N:3]1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CCN(C(C)C)C(C)C>C(#N)C>[CH3:13][O:12][C:10]([C@@H:7]1[C:6]2[N:14]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:15]=[CH:16][C:5]=2[C@H:4]2[CH2:9][N:8]1[C:2](=[O:1])[N:3]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:11]
Reactant: COC(=O)[C@@H]1c2[nH]ncc2[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)Cn1ncc2c1[C@@H](C(=O)OC)N1C[C@H]2N(OCc2ccccc2)C1=O
Temperature: 50 °C
Yield: 11.8 %

Procedure:
0.2 g of the product obtained in Stage K of Example 1 is dissolved in 2 ml of acetonitrile, in a round-bottomed flask. 0.150 μl of ethyl bromoacetate and 240 μl of DIEA are added. The medium is heated at 50° C. for 24 hours and then the reaction medium is extracted with ethyl acetate, the organic phase is washed with an aqueous tartaric acid solution at 10% and then with an aqueous NaCl solution. The organic phase is dried over magnesium sulfate, filtered off and the solvent is evaporated off under reduced pressure. 266 mg of the crude product are obtained which are purified by chromatography on silica, eluting with a methylene chloride/acetone/triethylamine, 95/0.5/0.1%, mixture. 37 mg of the isomer A, ethyl trans-4,5,6,8-tetrahydro-8-(methoxycarbonyl)-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-1-acetate having the empirical formula C20H22N4O6 are obtained (M=414.42 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18](=[O:29])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].[CH3:30][O:31][C:32]1[N:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][C:36](O)=[CH:35]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:29])[NH:19][C@H:20]1[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][O:28][C:36]2[CH:37]=[N:38][C:39]3[C:34]([CH:35]=2)=[N:33][C:32]([O:31][CH3:30])=[CH:41][CH:40]=3)[CH2:24][CH2:25]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCO)CC1
Reactant: COc1ccc2ncc(O)cc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(OCC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)cc2n1
Temperature: 30 °C
Reaction time: 14 h

Procedure:
Diethyl azodicarboxylate (3.96 g, 22.72 mmol, 3.0 eq) is added at room temperature to a stirred solution of [trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (1.84 g, 7.57 mmol, 1.0 eq), 6-methoxy-[1,5]naphthyridin-3-ol (1.80 g, 10.22 mmol, 1.35 eq) and triphenylphosphine (5.96 g, 22.72 mmol, 3.0 eq) in tetrahydrofuran (70 mL). After 14 hours stirring at 30° C., tetrahydrofuran is evaporated and the resulting crude product is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 6:1, v/v) to afford {trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as an off-white solid (1.65 g, 53.5% yield).