Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1([CH3:29])[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH:19]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[O:21][CH2:20]2)[CH2:13]1)=O)C.O>C1COCC1>[O:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[O:21][CH2:20][CH:19]1[CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][C:12]([CH2:10][OH:9])([CH3:29])[CH2:13]1
Reactant: CCOC(=O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(CO)CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a suspension of LiAlH4 (0.59 g, 15.54 mmol) in dry THF (45 ml), was added 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylic acid ethyl ester (1.0 g, 3.13 mmol) in dry THF (5 ml). The reaction mixture was refluxed for 1 h. Water was slowly added and the reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the desired product which, was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]([CH2:17][CH2:18][CH2:19][C:11]=2[CH:10]=1)=O.[C-]#N.[Li+]>O1CCCC1.CN(C)C=O>[C:5]([C:15]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=2)[CH2:19][CH2:18][CH:17]=1)#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [C-]#N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC=C2C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
Trimethylsilylcyanide (50.0 g, 510 mmol) was added to a suspension of 75.0 g (430 mmol) of 6-methoxy-α-tetralone (commercially available from Aldrich Chemical Company) in 75 mL of anhydrous tetrahydrofuran (THF) at ambient temperature. Lithium cyanide (100 mL of a 0.5M solution in N,N-dimethylformamide (DMF)) was added to the resultant mixture in one portion. The reaction mixture was stirred at ambient temperature for 1.5 h and then the THF was removed under reduced pressure. The concentrate was partitioned between diethyl ether and water (5:1 v/v). The aqueous layer was extracted with diethyl ether and the combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 400 mL of anhydrous toluene, containing 15 g of p-toluenesulfonic acid, previously refluxed in order to remove residual water by azeotropic distillation. The mixture was heated at reflux (with a Dean Stark trap) for 1 h. The resultant solution was cooled to ambient temperature and washed with cold 1N aqueous sodium hydroxide solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with 10% ethyl acetate in hexane to afford 48.09 g (60% yield) of the title compound. The physical properties of the product were identical to the properties reported for this compound by F. Z. Basha, et al. in J. Organic Chemistry, 50: 4160-2 (1985).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([OH:8])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:19]1[CH:24]=[CH:23][C:22]([N+]([O-])=O)=[CH:21][CH:20]=1>C(OCC)(=O)C.C(O)(C)(C)C>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([O:8][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC1CCC(C(C)C)C(Oc2ccccc2)C1

Procedure:
1.9 g of 2,6-difluorobenzoylisocyanate were added to a solution of 2.47 g of 4-dl-menthyloxy-aniline in a mixture of 15 ml of diethyl ether and 15 ml of petroleum ether (60-80) while stirring at room temperature. After adding 35 ml of petroleum ether (60-80), stirring was continued for another hour, after which the formed prepcipitate was sucked off, washed with petroleum ether and dried. The desired product was obtained in a yield of 4.1 g; melting-point 189°-190° C. The starting aniline was obtained from the corresponding nitro compound by reduction with hydrogen under the influence of Raney nickel as a catalyst, ethyl acetate being used as a solvent. 1-Nitro-4-dl-menthyloxybenzene was prepared by reaction of dl-menthol with 1-fluoro-4-nitrobenzene in tert.-butanol as a solvent in the presence of potassium tert.-butoxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[C:20]3[O:21][C:22]4[C:27]([C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[CH:10]=1.C(OCCO)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[C:20]3[O:21][C:22]4[C:27]([C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[CH:10]=1
Reactant: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccc(F)cc4F)ccn3)cccc12
Solvent: CCOCCO
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4F)ccn3)cccc12
Temperature: 130 °C

Procedure:
To a 250 mL flask added iridium complex (2.348 g, 3.29 mmol), 8-(4-(2,4-difluorophenyl)pyridin-2-yl)-2-methylbenzofuro[2,3-b]pyridine (2.45 g, 6.58 mmol), 2-ethoxyethanol (60 mL), DMF (60 mL). The mixture was heated in an oil bath at 130° C. overnight under N2 and allowed to cool and evaporated the solvents to leave a red/orange solid which was further purified by silica gel column to give orange solid 1.7 g (61% yield) desired product which was confirmed by LC-MS.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=O)[O:14]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:32]2)=CC=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH2:7]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[S:32])[O:14]2)[CH2:10][CH2:9]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: S=C1OC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Temperature: 140 °C

Procedure:
To a mixture of 1′-(phenylmethyl)-spiro[isobenzofuran-1(3H),4′-piperidin]-3-one (25 g, 85.2 mmol) [C.A.S. 37663-42-6] in toluene (600 ml), was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) (34.47 g, 85.2 mmol was added. The reaction mixture was heated at 140° C. for 2 h. After cooling, the mixture was poured into NH4Cl (aqueous sat. solution) and extracted with DCM. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/MeOH 3% as eluent). The desired fractions were collected and concentrated in vacuo to a residue that was purified by HPLC to yield intermediate D72 (8 g, 30.3%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[CH3:11][O-:12].[Na+]>CO>[CH3:11][O:12][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10]
Reactant: Cc1c(N)nnc(Cl)c1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nnc(N)c(C)c1C
Yield: 49 %

Procedure:
6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 500 mg, 3.17 mmol, 1.0 eq) in 14.51 mL of a 25% solution (w/w) of sodium methylate in MeOH was heated for 1 h at 130° C. in a single mode microwave oven. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried (Na2SO4 anh.). Volatile components were removed by the use of a rotary evaporator and the crude mixture was purified via MPLC (Biotage Isolera; 25 g SNAP NH2 cartridge: hexane→hexane/EtOAc 1/1) to give 250 mg (49% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:9][CH3:10])[NH:5][C:6]=1[CH2:7][OH:8]>CN(C)C=O.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[NH:3][C:4]([CH2:9][CH3:10])=[N:5][C:6]=1[CH:7]=[O:8]
Reactant: CCc1nc(Br)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Product: CCc1nc(C=O)c(Br)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.9 %

Procedure:
4-Bromo-2-ethyl-5-(hydroxymethyl)imidazole (18.9 g) was dissolved in dry dimethylformamide (189 ml), and manganese dioxide (80.1 g) was added. The mixture was stirred at room temperature for 5 hr and left standing overnight. The reaction mixture was filtered through celite and insoluble matter was washed with chloroform. The filtrate and washing were combined and concentrated to dryness under reduced pressure. The residue was washed with water to give 5-bromo-2-ethylimidazole-4-carbaldehyde (12.9 g) as a brown powder.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:7]([CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])[NH:8][C:9](=[O:29])[CH2:10][NH:11][C:12](=[O:28])[C@@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14]C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:38]([O:37][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]([CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:35])[NH2:36])[NH:8][C:9](=[O:29])[CH2:10][NH:11][C:12](=[O:28])[C@@H:13]([CH:25]([CH3:26])[CH3:27])[NH2:14])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOC(OCCCC)C(CCCNC(=N)N)NC(=O)CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCOC(OCCCC)C(CCCNC(=N)N)NC(=O)CNC(=O)[C@H](N)C(C)C
Yield: 136.1 %

Procedure:
132 mg of the N-benzyloxycarbonyl-D-valyl-glycyl-D,L-argininal dibutyl acetal was dissolved in 10 ml of methanol and subjected to catalytic reduction with palladium black for four hours. After the completion of the reaction, the palladium black was removed and the solvent was distilled off in vacuo to give 138 mg of D-valyl-glycyl-D,L-argininal dibutyl acetal in the form of a powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:20]([C:23]1[NH:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])[CH3:21].[I-].[Na+].[OH-].[Na+]>O.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][N:24]3[CH:25]=[CH:26][CH:27]=[C:23]3[C:20](=[O:22])[CH3:21])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(CCl)cs2)cc1OCC
Reactant: CC(=O)c1ccc[nH]1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(Cn3cccc3C(C)=O)cs2)cc1OCC
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
In a mixed solvent consisting of 2 ml of dimethylformamide and 0.2 ml of water were dissolved 200 mg of 2-(3,4-diethoxyphenyl)-4-chloromethylthiazole, 73 mg of 2-acetylpyrrole, 200 mg of sodium iodide and 200 mg of sodium hydroxide. The solution was stirred at 80° C. for 4 hours. The reaction mixture was subjected to distillation to remove the solvent. To the residue were added 30 ml of dichloromethane and 20 ml of water, and phase separation was conducted. The organic layer was washed with 15 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was recrystallized from methanol to obtain 60 mg of 2-(3,4-diethoxyphenyl)-4-(2-acetyl-1-pyrrolyl)methylthiazole as white acicular crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37].[CH3:38][N:39](C=O)[CH3:40]>C(Cl)Cl.CNC.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:39]([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37]
Reactant: CN(C)C=O
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: CNC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(N(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide, (0.054 g, 0.1 mmol) was dissolved in a mixture of DMF (0.5 mL) and CH2Cl2 (10 mL), and 40% dimethylamine in water (1 mL) was added. The mixture was stirred under argon at room temperature for 3 h. The solvents were pumped off in vacuo. The residue was flash chromatographed on silica gel (10 g) eluted with 10-60% EtOAc/CH2Cl2 to give the title compound as a white amorphous solid. The solid was crystallized from CH2Cl2/hexane to give the title compound as a white crystalline solid. mp 214-215° C.; LC-MS m/z 521 (M+H)+, 2.0 min (ret. time).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH3:30])[CH2:24]OS(C)(=O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:30][C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:16])([CH3:18])[CH3:17])[CH3:24])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cn1nccc1-c1cc(N)ccc1O
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C[C@@H](COc1ccc(N)cc1-c1ccnn1C)NC(=O)OC(C)(C)C
Yield: 34.6 %

Procedure:
4-Amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (300.00 mg, 1585.5 μmol), methanesulfonic acid 2-(S)-tert-butoxycarbonylamino-propyl ester (602.45 mg, 2378.3 μmol) and Cesium carbonate (1033.2 mg, 3171.0 μmol) were dissolved in acetone, and heated in the microwave at 130 C for 1 hour. The reaction mixture was filtered and the filtrate removed under vacuum. The residue was dissolved in DCM; washed with 1N NaOH (3×) and then removed under vacuum to yield a brownish residue in 34.6% yield. LCMS m/z=347.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.32 Hz, 3 H), 1.38 (s, 9 H), 3.65 (s, 3 H), 3.67-3.77 (m, 3 H), 6.23 (d, J=1.77 Hz, 1 H), 6.84 (s, 1 H), 6.95 (s, 1 H), 7.11 (s, 1 H), 7.44 (d, J=1.77 Hz, 1 H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][C:15]([NH:21][CH:22]=[O:23])=[N:14][C:13]=2[N:12]([C@@H:24]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[C@@H:26]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:25]2)[CH:11]=1>ClCl>[CH3:30][CH:29]([CH3:31])[C:28]([O:27][C@@H:26]1[C@@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[O:34][C@@H:24]([N:12]2[C:13]3[N:14]=[C:15]([NH:21][CH:22]=[O:23])[N:16]=[C:17]([O:19][CH3:20])[C:18]=3[C:10]([Cl:9])=[C:11]2[Cl:1])[CH2:25]1)=[O:32]
Reactant: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reactant: O=C1CCC(=O)N1Cl
Agent: ClCl
Product: COc1nc(NC=O)nc2c1c(Cl)c(Cl)n2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
N-Chlorosuccinimid e (117 mg, 0.9 mmol) is added to a solution of compound (45) (200 mg, 0.4 mmol in 5 ml of DMF). After it had been stirred (at room temperature for 16 h), the solution is added to a mixture of CH2 Cl2 /5% aq. NaHCO3 (50 ml, 9:1). The organic phase is separated off, washed with water, dried over Na2SO4, filtered and evaporated. The evaporated residue is dissolved in CH2Cl2 and this solution is chromatographed on silica gel (column: 5×20 cm, CH2Cl2 /acetone, 95:5). The main zone is separated off. Colorless crystals (149 mg, 72%) are obtained after evaporating off the solvent and crystallizing from cyclohexane. Melting point: 127°-128° C. 1H-NMR ([D6 ] DMSO): δ=1.01 (dd, CH3), 1.14 (d, J=7.0, CH3), 2.44, 2.47, 2.60, 3.53 (4 m, CH and Hα, ○ --C(2')), 4.05 (s, OCH3), 4.17 (m, H--C(5')), 4.30 (m, H--C(4')), 5.56 (m, H--C(3')), 6.41 (m, H--C(1')), 9.44 (d, J=9.1, NH), 10.94 (d, J=9.8, HCO). Anal. calculated for C21 H26Cl2N4O7 (517.4): C 48.75, H 5.07, N 10.83; found: C 49.04, H 5.09, N 10.66.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1CC[CH2:17][CH2:16]1.C([Mg]Cl)=C>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[CH:16]=[CH2:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Agent: C=C[Mg]Cl
Solvent: CCCCCC
Product: C=C[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 48 %

Procedure:
In an argon atmosphere, 6.54 g (28.1 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane and after adding a vinyl magnesium chloride tetrahydrofuran solution (1.61 mol/L, 34.5 mL, 55.5 mmol), the resulting solution was stirred at room temperature for 22 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 85° C./6.1×102 Pa) to obtain 1,3-di-tert-butyl-2-vinyl-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)CHCH2) as a yellow liquid (yielded amount: 3.01 g, yield: 48%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CC(C)(CO)CBr
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)(C)CO)c1OC
Temperature: 80 °C
Yield: 14.6 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.798 mmol) and 3-bromo-2,2-dimethylpropan-1-ol (134 mg, 0.798 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (15 mg, 14.7%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([Br:15])=[C:9]2[O:13][C:12]([CH3:14])=[N:11][C:10]=12)=O.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Br:15][C:8]1[C:9]2[O:13][C:12]([CH3:14])=[N:11][C:10]=2[C:5]([CH2:3][OH:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Br)c2oc(C)nc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nc2c(CO)ccc(Br)c2o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
To a solution of 7-bromo-2 methyl-benzo[d]oxazole-4-carboxylic acid methyl ester (8.64 g) in tetrahydrofuran (250 ml) was added dropwise a solution of diisobutylaluminium hydride (“DIBAL-H”) (1M in hexane) (80 ml) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes. Then the ice-bath was removed and the reaction mixture was allowed to warm to ambient temperature. After 40 minutes the mixture was cooled with an ice-bath and the reaction was quenched by the slow addition of water (5.0 ml). The mixture was poured onto aqueous sodium hydrogen carbonate (saturated) (300 ml) and extracted with diethyl ether (400 ml). The aqueous phase was further extracted with diethyl ether (2×300 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was triturated in a mixture of diisopropyl ether and heptane (3:1) to give (7-bromo-2-methyl-benzo[d]oxazol-4-yl)-methanol (4.45 g). 1H-NMR (400 MHz, CDCl3): 7.41 (d, 1H), 7.17 (d, 1H), 4.98 (s, 3H), 3.06 (s, 1H), 2.67 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([F:22])=[C:11]3[N:20]=[CH:19][N:18]([CH3:21])[C:12]3=[N:13][C:14]=2[C:15]([OH:17])=O)=[C:4]([F:23])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:45]([O:47][CH2:48][CH2:49][O:50][NH2:51])=[CH2:46]>CCOC(C)=O>[CH:45]([O:47][CH2:48][CH2:49][O:50][NH:51][C:15]([C:14]1[N:13]=[C:12]2[N:18]([CH3:21])[CH:19]=[N:20][C:11]2=[C:10]([F:22])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:23])=[O:17])=[CH2:46]
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)O)nc21
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1nc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
To a solution of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1.00 equivalent) and HOBt (1.50 equivalents) is added EDCI (1.50 equivalents) at room temperature. After stirring for 1 hour, O-(2-vinyloxy-ethyl)-hydroxylamine (1.10 equivalents) and TEA (1.20 equivalents) are added. The reaction mixture is stirred for 1 hour and diluted with EtOAc. The resulting mixture is washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is used directly without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[C:12]([CH2:13]Cl)=[N:11][C:10]([C:15]([OH:17])=[O:16])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([N:24]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[N:8]3[N:9]=[C:10]([C:15]([OH:17])=[O:16])[N:11]=[C:12]3[CH2:13]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1nc(CCl)n(-c2cccnc2Cl)n1
Reactant: NC1CCCCC1
Product: O=C(O)c1nc2n(n1)-c1cccnc1N(C1CCCCC1)C2

Procedure:
using 21.80 g (0.080 mol) of 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid and 35.70 g (0.360 mol) of cyclohexylamine there is obtained 5-cyclohexyl-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid and the methyl ester thereof which, after recrystallisation from methylene chloride/isopropanol, melts at 170°-176°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][OH:16])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][O:16][CH2:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:18]=1
Reactant: Cc1nn(C)c(Oc2ccc(Cl)cc2)c1C=NO
Reactant: COC(=O)c1ccccc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1CON=Cc1c(C)nn(C)c1Oc1ccc(Cl)cc1
Reaction time: 5 h
Yield: 64 %

Procedure:
2.0 Grams (0.00755 mole) of 5-(4-chlorophenoxy)-1,3-dimethyl-pyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dimethylformamide, and after adding 0.5 g (0.0125 mole) of powdery sodium hydroxide, the resulting mixture was thoroughly stirred. To this solution was added 1.73 g (0.00755 mole) of methyl 2-bromomethylbenzoate, and reaction was carried out at from 70° to 80° C. for 5 hours. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 2.0 g cf the desired compound.