Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:12][CH2:11]2)[C:3](=O)[NH:2]1.B.CO>C1COCC1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:12][CH2:11]2)[CH2:3][NH:2]1
Reactant: O=C1NC(=O)C2(CC2)c2ccccc21
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(c1)CNCC21CC1
Temperature: 0 °C

Procedure:
0.5 g (2.7 mmol) 1′H-spiro[cyclopropane-1,4′-isoquinoline]-1′,3′(2′H)-dione in 50 mL THF were heated to the reflux temperature of the solvent. 11 mL (11 mmol) of a 1M borane in THF solution were added dropwise and the mixture was refluxed for 3 h. The reaction mixture was cooled to 0° C. and mixed with 50 mL methanol. The reaction mixture was evaporated down, the residue was combined with 15 mL of a 4M hydrochloric acid solution and refluxed for 30 min. After neutralisation with 15 mL of an aqueous 4M sodium hydroxide solution the mixture was extracted twice with ethyl acetate. The combined organic phases were dried and evaporated down. The product was purified by HPLC. The product-containing fractions were combined and evaporated down.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH3:15].CO>>[N+:12]([C:11]1[C:2]([NH2:15])=[N:3][C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc2c(nc1Cl)CCCC2
Reactant: N
Solvent: CO
Product: Nc1nc2c(cc1[N+](=O)[O-])CCCC2
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of intermediate (9) (0.0658 mol) in NH3/CH3OH 7N (60 ml) was stirred at 120° C. for 12 hours in an autoclave. The solvent was evaporated till dryness. The residue was taken up in 2-propanone. The precipitate was filtered off and dried, yielding 8.6 g 5,6,7,8-tetrahydro-3-nitro-2-quinolinamine (intermediate 10). d) A mixture of intermediate (10) (0.031 mol) in methanol (100 ml) was hydrogenated at room temperature under a 3.105 Pa (3 bar) pressure for 30 minutes in a Parr apparatus. After uptake of hydrogen (3 equivalents), the catalyst was filtered through celite, rinced with methanol and the filtrate was evaporated till dryness. The product was used with further purification, yielding 5.07 g 5,6,7,8-tetrahydro-2,3-quinolinediamine (intermediate 11).
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.[F:12][C:13]1[C:18]([CH:19]=[O:20])=[C:17]([F:21])[CH:16]=[CH:15][C:14]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[OH-].[K+].Cl>CO>[C:10]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[C:3]([CH:19]([OH:20])[C:18]3[C:13]([F:12])=[C:14]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=4)(=[O:25])=[O:24])[CH:15]=[CH:16][C:17]=3[F:21])[C:4]=12)#[N:11]
Reactant: O=Cc1c(F)ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Reactant: N#Cc1ccnc2[nH]ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccnc2[nH]cc(C(O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Temperature: 25 °C
Reaction time: 46 h
Yield: 9.3 %

Procedure:
Into a round bottom flask 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (5, 0.054 g, 0.38 mmol), N-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (4, 0.179 g, 0.49 mmol), 0.75 mL of methanol and potassium hydroxide (0.103 g, 1.89 mmol) were combined. The reaction was stirred at room temperature for 46 hours, then neutralized with 0.1 N aqueous hydrochloric acid and extracted 3× with ethyl acetate. The organic layers were combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound (6, 0.018 g). MS (ESI) [M+H+]+=509.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:16]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:15]3[C:10](=[N:11][CH:12]=[C:13](I)[CH:14]=3)[O:9][C:5]2=[CH:6][C:7]=1[F:8].C[Si](C)(C)[C:25]#[C:26][C:27]1([CH3:31])[CH2:30][O:29][CH2:28]1.CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:16]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:25]#[C:26][C:27]4([CH3:31])[CH2:30][O:29][CH2:28]4)[CH:14]=3)[O:9][C:5]2=[CH:6][C:7]=1[F:8]
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: NC1=NC2(CO1)c1cc(Br)c(F)cc1Oc1ncc(I)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C#Cc2cnc3c(c2)C2(COC(N)=N2)c2cc(Br)c(F)cc2O3)COC1
Reaction time: 4 h
Yield: 42.2 %

Procedure:
A vial charged with Pd(PPh3)4 (0.73 g, 0.63 mmol), copper(I) iodide (0.48 g, 2.52 mmol), 7-bromo-8-fluoro-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (3.0 g, 6.30 mmol), trimethyl((3-methyloxetan-3-yl)ethynyl)silane (1.06 g, 6.30 mmol) and 13 mL DMF was degassed with argon and treated with DIPA (4.49 mL, 31.5 mmol). The resulting slurry was allowed to stir at RT for 18 h at which point an additional portion of copper(I) iodide (0.48 g, 2.52 mmol) was added. After stirring for an additional 4 h the reaction mixture was poured into water (50 mL) and was extracted with EtOAc (3×100 mL). The resulting suspension was filtered through a glass frit and the filtrate was dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography [0-50% (9:1 CH2Cl2:MeOH)/CH2Cl2] provided 7-bromo-8-fluoro-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (1.18 g, 2.66 mmol).
Reaction SMILES: O=[CH:2][CH2:3][C@H:4]([NH:11]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:19].[NH2:20][C:21]1([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.O>[ClH:19].[ClH:19].[NH2:11][C@H:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH2:2][NH:20][C:21]1([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)C1(N)CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)C1(NCC[C@H](N)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl [(1S)-3-oxo-1-phenylpropyl]carbamate from Step B (0.820 g, 3.29 mmol) and methyl 1-aminocyclopentanecarboxylate hydrochloride (0.591 g, 3.29 mmol) in chloroform (33 mL) was added Hunig's base (0.574 mL, 3.29 mmol). After stirring at ambient temperature for 20 min, NaHB(OAc)3 (1.74 g, 8.22 mmol) was added as a solid. Upon completion of the reaction, saturated aqueous NaHCO3 (3 mL) was added and the mixture was allowed to stir for at least 2 h. Water (5 mL) and additional saturated NaHCO3 (3 mL) was then added to form two layers. The aqueous layer was extracted once with chloroform (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM 1:99 to 6:94, to give the title compound. MS: nm/z=377 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)C=C(N2CCCCC2)CC(C)(C)N1
Yield: 21 %

Procedure:
154.7 g of 2,2,6,6-tetramethyl-4-piperidone, 160 g of piperidine and 10.0 g of p-toluenesulphonic acid monohydrate were dissolved in 200 ml of benzene. The solution was refluxed by heating for 8.5 hours, whilst the water formed in situ was removed by means of a Dean-Stark separator. The reaction mixture was then poured into a mixture of 700 ml of water, 200 ml of concentrated aqueous ammonia and 100 g of ice. The organic layer was separated, washed three times with water and then dried over magnesium sulphate. After removal of the solvent, the residue was distilled under reduced pressure, giving 46.6 g of 1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine (bp 80° - 82° C/1 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(C=O)c3)ccc2-n2c(C)nnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(CN4CCCC4)c3)ccc2-n2c(C)nnc21
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(3-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 5) (95 mg) was dissolved in DCM (5 ml). Pyrrolidine (24 μl) and acetic acid (8.62 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (202 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, overnight. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. over the weekend to give (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(3-(pyrrolidin-1-ylmethyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (71.7 mg) as a white solid. LCMS (formate): MH+ 553/555, RT 0.76 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:5]([N:7]([CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:9][C:10](O)=[O:11])=[O:6].[CH3:21][N:22](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:5]([N:7]([CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:9][C:10](=[O:11])[NH:22][CH3:21])=[O:6]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1cc(Cl)cc(C(=O)N(CCC(=O)O)C(C)C)c1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CCN(C(=O)c1cc(Cl)cc(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
To a stirred solution of 3-[(3-chloro-5-methoxy-benzoyl)-isopropyl-amino]-propionic acid (0.600 g), TBTU (1.28 g) in DMF (10 ml) was added DIPEA (0.696 ml) followed a 2M solution of methylamine in THF (8.0 ml) after 10 min. The reaction mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with further water and 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the title compound as a brown oil (0.575 g).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][S+](C)C)=[O:6])[CH3:3].N12CCCN=C1CCCCC2.[C:22]1(=[O:27])[CH2:26][CH2:25][CH:24]=[CH:23]1.COC(C)(C)C>C(#N)C>[O:27]=[C:22]1[CH2:26][CH2:25][CH:24]2[CH:23]1[C@H:7]2[C:5]([O:4][CH2:2][CH3:3])=[O:6]
Reactant: O=C1C=CCC1
Reactant: CCOC(=O)C[S+](C)C
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)[C@H]1C2CCC(=O)C21
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a suspension of (ethoxycarbonylmethyl)dimethyl sulfonium bromide (134 g, 585 mmol) in 486 mL of acetonitrile at room temperature is added 87.4 mL (585 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene dropwise over 15 minutes. After stirring for 1 hour, the yellow mixture is treated with 40 g (487 mmol) of 2-cyclopenten-1-one over 10 minutes. The mixture is allowed to stir over night at which time 480 mL of tert-butyl methyl ether is added, followed by washing with 1N hydrochloric acid (1×240 mL). The aqueous layer was washed with tert-butyl methyl ether (1×240 mL). The combined organic extracts were washed with brine (1×400 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide crude ethyl (6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate as an orange solid (84.8 g). The crude material may be purified through distillation (˜138° C., 10 mm Hg), followed by slurrying the solidified distillate in heptane, filtering, and drying.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH3:7][O:8][C:9](=[O:22])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=2)[CH:14]=[N:13][CH:12]=1>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:8][C:9](=[O:22])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:19]=2)[CH:14]=[N:13][CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1cncc2ccc(Br)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cncc2ccc(C#C[Si](C)(C)C)cc12
Temperature: 45 °C

Procedure:
Trimethylsilylacetylene (0.17 ml, 1.23 mmol) is added to a suspension of (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (0.325 g, 1.03 mmol) in DMF (1.75 ml) and triethylamine (10 ml), follwed by copper(I) iodide (40 mg, 0.20 mmol) and (Ph3P)2PdCl2 (73 mg, 0.10 mmol). The reaction is heated at 45° C. for 40 minutes, cooled to ambient temperature and diluted with ethyl acetate. After washing with water and brine, the organic phase is dried over magnesium sulfate, evaporated and purified by flash column chromatography (1:1 ethyl acetate-hexane elution) to afford (6-trimethylsilanylethynyl-isoquinolin-4-yl)-acetic acid methyl ester, [MH]+ 298. This intermediate (0.221 g, 0.74 mmol) is dissolved in methanol (7.5 ml) and treated with potassium carbonate (75 mg, 0.54 mmol). The reaction is stirred for 30 minutes at ambient temperature, evaporated and purified by flash chromatography (5:1 dichloromethane-methanol elution) to afford (6-ethynyl-isoquinolin-4-yl)-acetic acid, [MH]+ 212.
Reaction SMILES: [K+].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8](=[S:11])([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]([O:22][CH3:23])([O:20][CH3:21])[CH2:16][CH2:17][CH2:18]Br.C1OCCOCCOCCOCCOCCOC1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8](=[S:11])([O:10][CH2:18][CH2:17][CH2:16][C:15]([O:22][CH3:23])([O:20][CH3:21])[O:14][CH3:13])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(CCCBr)(OC)OC
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(CCCOS(=O)(=S)c1ccc(C)cc1)(OC)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.3 %

Procedure:
A suspension of para-toluenethiosulphonic acid potassium salt (8.77 g), trimethyl 4-bromoorthobutyrate (8.00 g) and 18-crown-6 (10.24 g) in anhydrous tetrahydrofuran (60 ml) was ultrasonicated for 5 minutes then stirred at room temperature for 3 days. The mixture was poured into saturated aqueous sodium bicarbonate solution (200 ml) and extracted with ether (2×200 ml). The organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the subtitle compound (10.52 g) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17](OC)=[O:18])=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)ncn2Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
0.87 g of methyl 1-benzyl-5-benzimidazolecarboxylate (prepared as described in Preparation 27) in 18 ml of dehydrated tetrahydrofuran were added to a suspension of 0.23 g of lithium aluminum hydride in 10 ml of dehydrated tetrahydrofuram, whilst ice-cooling, and the resulting mixture was stirred for 2 hours at room temperature. A further 0.11 g of lithium aluminum hydride and 10 ml of dehydrated tetrahydrofuran were then added to the reaction mixture and the mixture was stirred for 1 hour at room temperature and then for 4.5 hours at 50° C. in oil bath, after which it was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature by allowing it to stand, after which sodium sulfate decahydrate was added to it in excess and the mixture was stirred for 2 hours at room temperature. At the end of this time, the reaction mixture was filtered with the aid of a Celite (trade mark) filter aid and the filtrate was freed from the solvent by distillation under reduced pressure. The residue was then recrystallized from a mixture of ethanol and diisopropyl ether, to give 383 mg of the title compound, melting at 148°-150° C.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]C=C>O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:1]([O:4][C@@H:5]([CH3:11])[C:6]([O:8][CH2:9][CH2:10][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCCCCCCCCO
Reactant: C=CCOC(C)C(=O)OCC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: O
Product: C=CCCCCCCCCOC(=O)[C@H](C)OCC=C
Temperature: 80 °C
Reaction time: 5 h
Yield: 80.4 %

Procedure:
3.0 g (19 mmol) of ethyl 2-allyloxypropionate are introduced into 4.5 g (28.5 mmol) of 9-decen-1-ol, and 0.56 g (2 mmol) of Ti(OiPr)4 are added. The mixture is then heated to 80° C. and stirred at a reduced pressure of 400 mbar for 5 h. A few drops of water are then added and the crude product is purified by means of flash chromatography (cyclohexane/EtOAc=25:1; Rf=0.21), giving 4.1 g (81%) of a colorless oil.
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18](S(C1C=CC=CC=1)(=O)=O)[CH2:17][CH2:16]2.O>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:18][CH:17]=[CH:16]2
Reactant: CCOC(=O)C1c2ccc(Br)cc2CCN1S(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)c1nccc2cc(Br)ccc12
Reaction time: 18 h
Yield: 58.9 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (762.3 μL, 5.10 mmol) was added to ethyl 6-bromo-2-(phenylsulfonyl)-1,2,3,4-tetrahydro-1-isoquinolinecarboxylate (1.03 g, 2.43 mmol) in toluene (12 mL) under argon and the reaction was stirred for 18 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:3 ethyl acetate:hexanes to give 400.6 mg (59%) of ethyl 6-bromo-1-isoquinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.63 (d, J=6 Hz, 1H), 8.43 (d, J=2 Hz, 1H), 8.41 (d, J=10 Hz, 1H), 8.05 (d, J=6 Hz, 1H), 7.91 (dd, J=9, 2 Hz, 1H), 4.46 (q, J=7 Hz, 2H), 1.37 (t, J=7 Hz, 3H). ESI-LCMS m/z 280 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CO)cn1
Reaction time: 0.33 h
Yield: 82.7 %

Procedure:
A solution of methyl 6-methylnicotinate (50 g, 0.33 mol) in anhydrous tetrahydrofuran (100 ml) was slowly added dropwise to a suspension of LAH (12.6 g, 0.33 mol) in anhydrous tetrahydrofuran (500 ml) over a period of 30 minutes while cooling on ice, and the mixture was stirred at the same temperature for 1 hour and 20 minutes. After confirming completion of the reaction by thin layer chromatography, H2O (25 ml) was slowly added dropwise over a period of 30 minutes while cooling on ice, and the stirring was continued at room temperature for 30 minutes. Magnesium sulfate was added for drying, and the precipitate was filtered through celite and washed three times with ethyl acetate. The solvent was distilled off under reduced pressure to yield the title compound (33.6 g, 82%) as a yellow oil.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:19][CH:18]=1.O.Cl>O1CCCC1.C(O)C>[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:42][CH:43]=1
Reactant: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3cccs3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
Lithium hydroxide monohydrate (153 mg) was added to a solution of ethyl E-8-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoate (682 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.7 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoic acid (567 mg, yield 87%) as colorless crystals. m.p. 106-108° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[CH2:3][O:2][CH3:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COCc1cc([N+](=O)[O-])ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 0 °C

Procedure:
18.3 g of 2-methoxymethyl-4-nitrophenol (1) (0.1 mol), 8.3 g (0.06 mol) of potassium carbonate and 40 ml of dimethylformamide were heated on a boiling water bath, and 12.1 ml (0.105 mol) of benzyl chloride were added over 10 minutes. After heating for 1 hour on the boiling water bath, the mixture was poured onto 150 g of ice. The yellow-brown crystals formed were filtered off, reslurried in ice-cold water and washed with petroleum ether. The wet product was recrystallized from 75 ml of isopropanol to give, after drying, 21 g of expected product with a melting point of 108° C. The results of the elementary analyses were as follows: